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【结 构 式】 
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【分子编号】37681 【品名】(4S)-4-hydroxydihydro-2(3H)-furanone; (S)-3-Hydroxy-gamma-butyrolactone 【CA登记号】7331-52-4 |
【 分 子 式 】C4H6O3 【 分 子 量 】102.08984 【元素组成】C 47.06% H 5.92% O 47.02% |
合成路线1
该中间体在本合成路线中的序号：(I)1) The cyclization of 4(S)-hydroxytetrahydrofuran-2-one (I) with the benzylideneimine derivative (II) by means of LDA gives the trans-azetidinone (III), which is separated from its cis-isomer by crystallization. The oxidation of (III) with NaIO4 in acetonitrile yields the carbaldehyde (IV), which is condensed with the silylated enol ether (V), prepared from 4'-fluoroacetophenone (VI), Li and TMSCl, to afford compound (VII). The dehydration of (VII) by means of TsOH gives the enone (VIII), which is hydrogenated and debenzylated with H2 over Pd/C in ethanol, providing the saturated ketone (IX). Finally, this compound is enantioselectively reduced with borane and the chiral catalyst (R)-1-methyl-3,3-diphenylperhydropyrrolo[1,2-c][1,3,2]oxaazaborole (CBS). 2) Alternatively, the reduction of enone (VIII) with H2 over RhCl(PPh3)3 in dichloromethane gives the benzylated saturated ketone (X), which is enantioselectively reduced with borane and CBS, yielding the benzylated alcohol (XI). Finally, this compound is debenzylated with H2 over Pd/C in ethanol.
| 【1】 Wu, G.-Z.; Chen, X.; Wong, Y.-S.; Schumacher, D.P.; Steinman, M.; 3-Hydroxy gamma-lactone based enantioselective synthesis of azetidinones. US 5886171 . |
| 【2】 Castañer, R.M.; Sorbera, L.A.; Castañer, J.; Ezetimibe. Drugs Fut 2000, 25, 7, 679. |
| 【3】 Wu, G.Z.; Chen, X.; Ding, Z.; Wong, Y.S.; A novel one-step diastereo- and enantioselective formation of trans-azetidinones and its application to the total synthesis of cholesterol absorption inhibitors. J Org Chem 1999, 64, 10, 3714. |
| 【4】 Steinman, M.; Schumacher, D.P.; Chen, X.; Wu, G.-Z.; Wong, Y.-S. (Schering Corp.); 3-Hydroxy gamma-lactone based enantioselective synthesis of azetidinones. WO 9745406 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| trans-(X) | 20656 | (3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]-2-azetidinone | C31H25F2NO3 | 详情 | 详情 | |
| trans-(III) | 37682 | (3S,4S)-4-[4-(benzyloxy)phenyl]-3-[(1S)-1,2-dihydroxyethyl]-1-(4-fluorophenyl)-2-azetidinone | C24H22FNO4 | 详情 | 详情 | |
| trans-(IV) | 37683 | (2S,3S)-2-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-4-oxo-3-azetidinecarbaldehyde | C23H18FNO3 | 详情 | 详情 | |
| trans-(VIII) | 37686 | (3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[(E)-3-(4-fluorophenyl)-3-oxo-1-propenyl]-2-azetidinone | C31H23F2NO3 | 详情 | 详情 | |
| trans-(VII) | 37687 | (3S,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[(1R)-3-(4-fluorophenyl)-1-hydroxy-3-oxopropyl]-2-azetidinone | C31H25F2NO4 | 详情 | 详情 | |
| trans-(IX) | 37688 | (3R,4S)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]-4-(4-hydroxyphenyl)-2-azetidinone | C24H19F2NO3 | 详情 | 详情 | |
| (I) | 37681 | (4S)-4-hydroxydihydro-2(3H)-furanone; (S)-3-Hydroxy-gamma-butyrolactone | 7331-52-4 | C4H6O3 | 详情 | 详情 |
| (II) | 37689 | N-[(Z)-[4-(benzyloxy)phenyl]methylidene]-4-fluoroaniline; N-[(Z)-[4-(benzyloxy)phenyl]methylidene]-N-(4-fluorophenyl)amine | C20H16FNO | 详情 | 详情 | |
| (V) | 37685 | [[1-(4-fluorophenyl)vinyl]oxy](trimethyl)silane; 1-(4-fluorophenyl)vinyl trimethylsilyl ether | C11H15FOSi | 详情 | 详情 | |
| (VI) | 37684 | 1-(4-fluorophenyl)-1-ethanone | 403-42-9 | C8H7FO | 详情 | 详情 |
| (XI) | 20657 | (3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-2-azetidinone | C31H27F2NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)
| 【1】 Wu GZ. Chen X，Wong YS et al.1999.3-hydroxy gamma-lactone based enaptiolelective synthesis of azetidinones. US 5886171 |
| 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) | 20651 | N-[(E)-[4-(benzyloxy)phenyl]methylidene]-4-fluoroaniline; N-[(E)-[4-(benzyloxy)phenyl]methylidene]-N-(4-fluorophenyl)amine | C20H16FNO | 详情 | 详情 | |
| (II) | 37681 | (4S)-4-hydroxydihydro-2(3H)-furanone; (S)-3-Hydroxy-gamma-butyrolactone | 7331-52-4 | C4H6O3 | 详情 | 详情 |
| (III) | 20653 | 3-[(2S,3R)-2-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-4-oxoazetidinyl]propionic acid | C25H22FNO4 | 详情 | 详情 | |
| (IV) | 37683 | (2S,3S)-2-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-4-oxo-3-azetidinecarbaldehyde | C23H18FNO3 | 详情 | 详情 | |
| (V) | 37685 | [[1-(4-fluorophenyl)vinyl]oxy](trimethyl)silane; 1-(4-fluorophenyl)vinyl trimethylsilyl ether | C11H15FOSi | 详情 | 详情 | |
| (VI) | 20656 | (3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]-2-azetidinone | C31H25F2NO3 | 详情 | 详情 | |
| (VII) | 37688 | (3R,4S)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]-4-(4-hydroxyphenyl)-2-azetidinone | C24H19F2NO3 | 详情 | 详情 | |
| (VIII) | 20631 | (R)-Methyl oxazaborolidine; (3aR)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole | 112022-83-0 | C18H20BNO | 详情 | 详情 |