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【结 构 式】 
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【分子编号】57766 【品名】9-benzyl 1-methyl (Z)-2-(tetrahydro-2H-pyran-2-yloxy)-2-nonenedioate 【CA登记号】 |
【 分 子 式 】C22H30O6 【 分 子 量 】390.4766 【元素组成】C 67.67% H 7.74% O 24.58% |
合成路线1
该中间体在本合成路线中的序号：(V)The known methyl 7-hydroxyheptanoate (I) is hydrolyzed with LiOH and subsequently converted to the benzyl ester (II) by treatment with benzyl bromide and NaHCO3. Swern oxidation of the primary alcohol function of (II) yields aldehyde (III), which is subjected to Wadsworth-Emmons condensation with the tetrahydropyranyl-protected phosphonate (IV) to afford the O-tetrahydropyranyl enol ether (V). Further acidic hydrolysis of (V) provides keto diester (VI). Alternatively, aldehyde (III) is condensed with the silyl-protected phosphonate (VII) to give (VIII), which is then deprotected to (VI) by desilylation with CsF. Displacement of the methyl ester function of (VI) with methylamine yields amide (IX). The benzyl ester group of (IX) is then removed by hydrogenolysis over Pd/C to produce acid (X). Finally, coupling of acid (X) with the thiazolyl amine (XI) leads to the title compound.
| 【1】 Garland, R.B.; Curtin, M.L.; Frey, R.R.; et al.; Electrophilic ketone-based histone deacetylase inhibitors as cancer chemotherapeutic agents. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 121. |
| 【2】 Holms, J.H.; Davidsen, S.K.; Michaelides, M.R.; Guo, Y.; Heyman, H.R.; Curtin, M.L.; Wada, C.K.; Dai, Y.; Vasudevan, A.; Frey, R.R.; Ji, Z. (Abbott Laboratories Inc.); Inhibitors of histone deacetylase. WO 0246129 . |
| 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) | 57762 | methyl 7-hydroxyheptanoate | C8H16O3 | 详情 | 详情 | |
| (II) | 57763 | benzyl 7-hydroxyheptanoate | C14H20O3 | 详情 | 详情 | |
| (III) | 57764 | benzyl 7-oxoheptanoate | C14H18O3 | 详情 | 详情 | |
| (IV) | 57765 | methyl 2-(dimethoxyphosphoryl)-2-(tetrahydro-2H-pyran-2-yloxy)acetate | C10H19O7P | 详情 | 详情 | |
| (V) | 57766 | 9-benzyl 1-methyl (Z)-2-(tetrahydro-2H-pyran-2-yloxy)-2-nonenedioate | C22H30O6 | 详情 | 详情 | |
| (VI) | 57768 | 9-benzyl 1-methyl 2-oxononanedioate | C17H22O5 | 详情 | 详情 | |
| (VII) | 57767 | methyl 2-{[tert-butyl(dimethyl)silyl]oxy}-2-(dimethoxyphosphoryl)acetate | C11H25O6PSi | 详情 | 详情 | |
| (VIII) | 57769 | 9-benzyl 1-methyl (Z)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-nonenedioate | C23H36O5Si | 详情 | 详情 | |
| (IX) | 57770 | benzyl 9-(methylamino)-8,9-dioxononanoate | C17H23NO4 | 详情 | 详情 | |
| (X) | 57771 | 9-(methylamino)-8,9-dioxononanoic acid | C10H17NO4 | 详情 | 详情 | |
| (XI) | 11042 | 4-(4-Methoxy-phenyl)-thiazol-2-ylamine; 4-(4-methoxyphenyl)-1,3-thiazol-2-ylamine; 4-(4-methoxyphenyl)-1,3-thiazol-2-amine | 2104-04-3 | C10H10N2OS | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)The known methyl 7-hydroxyheptanoate (I) is hydrolyzed with LiOH and subsequently converted to the benzyl ester (II) by treatment with benzyl bromide and NaHCO3. Swern oxidation of the primary alcohol function of (II) yields aldehyde (III), which is subjected to Wadsworth-Emmons condensation with the tetrahydropyranyl-protected phosphonate (IV) to afford the O-tetrahydropyranyl enol ether (V). Further acidic hydrolysis of (V) provides keto diester (VI). Alternatively, aldehyde (III) is condensed with the silyl-protected phosphonate (VII) to give (VIII), which is then deprotected to (VI) by desilylation with CsF. Displacement of the methyl ester function of (VI) with methylamine yields amide (IX). The benzyl ester group of (IX) is then removed by hydrogenolysis over Pd/C to produce acid (X). Finally, coupling of acid (X) with the thiazolyl amine (XI) leads to the title compound.
| 【1】 Garland, R.B.; Curtin, M.L.; Frey, R.R.; et al.; Electrophilic ketone-based histone deacetylase inhibitors as cancer chemotherapeutic agents. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 121. |
| 【2】 Holms, J.H.; Davidsen, S.K.; Michaelides, M.R.; Guo, Y.; Heyman, H.R.; Curtin, M.L.; Wada, C.K.; Dai, Y.; Vasudevan, A.; Frey, R.R.; Ji, Z. (Abbott Laboratories Inc.); Inhibitors of histone deacetylase. WO 0246129 . |
| 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) | 57762 | methyl 7-hydroxyheptanoate | C8H16O3 | 详情 | 详情 | |
| (II) | 57763 | benzyl 7-hydroxyheptanoate | C14H20O3 | 详情 | 详情 | |
| (III) | 57764 | benzyl 7-oxoheptanoate | C14H18O3 | 详情 | 详情 | |
| (IV) | 57765 | methyl 2-(dimethoxyphosphoryl)-2-(tetrahydro-2H-pyran-2-yloxy)acetate | C10H19O7P | 详情 | 详情 | |
| (V) | 57766 | 9-benzyl 1-methyl (Z)-2-(tetrahydro-2H-pyran-2-yloxy)-2-nonenedioate | C22H30O6 | 详情 | 详情 | |
| (VI) | 57768 | 9-benzyl 1-methyl 2-oxononanedioate | C17H22O5 | 详情 | 详情 | |
| (VII) | 57767 | methyl 2-{[tert-butyl(dimethyl)silyl]oxy}-2-(dimethoxyphosphoryl)acetate | C11H25O6PSi | 详情 | 详情 | |
| (VIII) | 57769 | 9-benzyl 1-methyl (Z)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-nonenedioate | C23H36O5Si | 详情 | 详情 | |
| (IX) | 57770 | benzyl 9-(methylamino)-8,9-dioxononanoate | C17H23NO4 | 详情 | 详情 | |
| (X) | 57771 | 9-(methylamino)-8,9-dioxononanoic acid | C10H17NO4 | 详情 | 详情 | |
| (XI) | 57772 | 4-{4-[2-(dimethylamino)ethoxy]phenyl}-1,3-thiazol-2-amine; N-{2-[4-(2-amino-1,3-thiazol-4-yl)phenoxy]ethyl}-N,N-dimethylamine | C13H17N3OS | 详情 | 详情 |