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【结 构 式】 
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【分子编号】19151 【品名】(1R,2S)-2-phenylcyclohexyl 2-[(triisopropylsilyl)oxy]acetate 【CA登记号】 |
【 分 子 式 】C23H38O3Si 【 分 子 量 】390.63842 【元素组成】C 70.72% H 9.8% O 12.29% Si 7.19% |
合成路线1
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) | 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2
该中间体在本合成路线中的序号：(IV)Reaction of benzyloxyacetyl chloride (I) with (-)-trans-2-phenylcyclohexanol (II) afforded chiral ester (III). Subsequent removal of the benzyl group by hydrogenolysis, followed by protection with triisopropylsilyl chloride and imidazole in DMF provided silyl ether (IV). Treatment of (IV) with LDA in THF at -85 C generated the corresponding enolate, which was cyclocondensed with imine (VII), (obtained from 3-methylbutenal (V) and p-anisidine (VI)), to produce azetidinone (VIII). Then, the N-p-methoxyphenyl group was removed by treatment with cerium ammonium nitrate in cold ACN-H2O, and the resulting azetidinone (IX) was coupled with di-tert-butyl dicarbonate in the presence of DMAP and Et3N to yield (X).
| 【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 |
|---|---|---|---|---|---|---|
| (I) | 10493 | 2-(Benzyloxy)acetyl chloride; Benzyloxyacetyl chloride | 19810-31-2 | C9H9ClO2 | 详情 | 详情 |
| (II) | 10492 | (1S,2R)-(+)-trans-2-Phenyl-1-cyclohexanol; (1S,2R)-2-Phenylcyclohexanol | 2362-61-0 | C12H16O | 详情 | 详情 |
| (III) | 10494 | (1S,2R)-2-phenylcyclohexyl 2-(benzyloxy)acetate | C21H24O3 | 详情 | 详情 | |
| (IV) | 19151 | (1R,2S)-2-phenylcyclohexyl 2-[(triisopropylsilyl)oxy]acetate | C23H38O3Si | 详情 | 详情 | |
| (V) | 19152 | 3-methyl-2-butenal | 107-86-8 | C5H8O | 详情 | 详情 |
| (VI) | 10478 | p-Anisidine; 4-Methoxyaniline; 4-Methoxyphenylamine | 104-94-9 | C7H9NO | 详情 | 详情 |
| (VII) | 19154 | 4-methoxy-N-[(E)-3-methyl-2-butenylidene]aniline; N-(4-methoxyphenyl)-N-[(E)-3-methyl-2-butenylidene]amine | C12H15NO | 详情 | 详情 | |
| (VIII) | 19155 | (3R,4S)-1-(4-methoxyphenyl)-4-(2-methyl-1-propenyl)-3-[(triisopropylsilyl)oxy]-2-azetidinone | C23H37NO3Si | 详情 | 详情 | |
| (IX) | 19156 | (3R,4S)-4-(2-methyl-1-propenyl)-3-[(triisopropylsilyl)oxy]-2-azetidinone | C16H31NO2Si | 详情 | 详情 | |
| (X) | 19157 | tert-butyl (2S,3R)-2-(2-methyl-1-propenyl)-4-oxo-3-[(triisopropylsilyl)oxy]-1-azetidinecarboxylate | C21H39NO4Si | 详情 | 详情 |
合成路线3
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). Ozonolysis of the olefinic bond of (IV) at -78 C in CH2Cl2-MeOH, followed by reductive workup using Me2S afforded aldehyde (V). Subsequent treatment of (V) with diethylaminosulfur trifluoride in CH2Cl2 at r.t. yielded the difluoromethyl lactam (VI). Then, the N-p-methoxyphenyl group of (VI) was removed by oxidative treatment with ceric ammonium nitrate at -5 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. |
| 【2】 Ferlini, C.; Scambia, G.; Lin, S.; Bernacki, R.J.; Ojima, I.; Wang, T.; Pera, P.; Slater, J.C.; Syntheses and biological activity of C3'-difluoromethyl taxoids. 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 39. |
| 【3】 Pera, P.; Scambia, G.; Ojima, I.; Lin, S.; Wang, T.; Ferlini, C.; Slater, J.C.; Bernacki, R.J.; Syntheses and biological activity of C-3'-difluoromethyl-taxoids. Bioorg Med Chem Lett 2000, 8, 7, 1619. |
| 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 | |
| (III) | 19154 | 4-methoxy-N-[(E)-3-methyl-2-butenylidene]aniline; N-(4-methoxyphenyl)-N-[(E)-3-methyl-2-butenylidene]amine | C12H15NO | 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) | 21733 | (2R,3R)-1-(4-methoxyphenyl)-4-oxo-3-[(triisopropylsilyl)oxy]-2-azetidinecarbaldehyde | C20H31NO4Si | 详情 | 详情 | |
| (VI) | 21734 | (3R,4R)-4-(difluoromethyl)-1-(4-methoxyphenyl)-3-[(triisopropylsilyl)oxy]-2-azetidinone | C20H31F2NO3Si | 详情 | 详情 | |
| (VII) | 21735 | tert-butyl (2R,3R)-2-(difluoromethyl)-4-oxo-3-[(triisopropylsilyl)oxy]-1-azetidinecarboxylate | C18H33F2NO4Si | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VIII)Ring opening of cyclohexene oxide (I) with phenylmagnesium bromide in the presence of CuI, followed by acetylation of the resulting alcohol (II) gave the racemic trans-2-phenylcyclohexyl acetate (III). Enzymatic resolution of (III) using porcine liver acetone powder yielded the desired (-)-alcohol (II) along with unreacted (+)-acetate (III). Condensation of the sodium alkoxide of benzyl alcohol with bromoacetic acid (IV) afforded benzyloxyacetic acid (V), which was then coupled with the chiral alcohol (-)-(II) to give ester (VI). Hydrogenolysis of the O-benzyl group of (VI), followed by silylation of the resulting hydroxyacetate ester (VII) with triisopropylsilyl chloride, furnished (VIII). Imine (XI) was prepared by condensation of 3-methyl-2-butenal (IX) with p-anisidine (X). The asymmetric cyclocondensation reaction of the lithium enolate derived from ester (VIII) with imine (XI) yielded the chiral beta-lactam (XII). Oxidative removal of the p-methoxyphenyl protecting group of (XII) and then reprotection of the lactam N atom with Boc2O furnished the intermediate N-Boc lactam (XIII).
| 【1】 Strum, M.; Tynebor, R.; Pera, P.; Bernacki, R.J.; Ojima, I.; Synthesis and SAR of advanced second generation taxoids. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 132. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (rac)-(III) | 51206 | (1R,2S)-2-phenylcyclohexyl acetate | C14H18O2 | 详情 | 详情 | |
| (rac)-(II) | 51208 | (1R,2S)-2-phenylcyclohexanol | C12H16O | 详情 | 详情 | |
| (-)-(II) | 51209 | (-)-(1R,2S)-2-phenylcyclohexanol | C12H16O | 详情 | 详情 | |
| (+)-(III) | 51210 | (1S,2R)-2-phenylcyclohexyl acetate | C14H18O2 | 详情 | 详情 | |
| (I) | 17986 | 7-oxabicyclo[4.1.0]heptane; cyclohexene oxide | 286-20-4 | C6H10O | 详情 | 详情 |
| (IV) | 23660 | 2-Bromoacetic acid | 79-08-3 | C2H3BrO2 | 详情 | 详情 |
| (V) | 51207 | 2-(benzyloxy)acetic acid | C9H10O3 | 详情 | 详情 | |
| (VI) | 51211 | (1R,2S)-2-phenylcyclohexyl 2-(benzyloxy)acetate | C21H24O3 | 详情 | 详情 | |
| (VII) | 51212 | (1R,2S)-2-phenylcyclohexyl 2-hydroxyacetate | C14H18O3 | 详情 | 详情 | |
| (VIII) | 19151 | (1R,2S)-2-phenylcyclohexyl 2-[(triisopropylsilyl)oxy]acetate | C23H38O3Si | 详情 | 详情 | |
| (IX) | 19152 | 3-methyl-2-butenal | 107-86-8 | C5H8O | 详情 | 详情 |
| (X) | 10478 | p-Anisidine; 4-Methoxyaniline; 4-Methoxyphenylamine | 104-94-9 | C7H9NO | 详情 | 详情 |
| (XI) | 19154 | 4-methoxy-N-[(E)-3-methyl-2-butenylidene]aniline; N-(4-methoxyphenyl)-N-[(E)-3-methyl-2-butenylidene]amine | C12H15NO | 详情 | 详情 | |
| (XII) | 19155 | (3R,4S)-1-(4-methoxyphenyl)-4-(2-methyl-1-propenyl)-3-[(triisopropylsilyl)oxy]-2-azetidinone | C23H37NO3Si | 详情 | 详情 | |
| (XIII) | 19157 | tert-butyl (2S,3R)-2-(2-methyl-1-propenyl)-4-oxo-3-[(triisopropylsilyl)oxy]-1-azetidinecarboxylate | C21H39NO4Si | 详情 | 详情 |