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【结 构 式】 
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【分子编号】14743 【品名】ethyl 4-[2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethoxy]ethoxy]-3-oxobutanoate 【CA登记号】 |
【 分 子 式 】C18H21NO7 【 分 子 量 】363.36728 【元素组成】C 59.5% H 5.83% N 3.85% O 30.82% |
合成路线1
该中间体在本合成路线中的序号：(I)A synthesis of S-12968 has been published: The cyclization of 4-[2-(2-phthalimidoethoxy)ethoxy]-3-oxobutyric acid ethyl ester (I) with 2-(2,3-dichlorobenzylidene)-3-oxobutyric acid 2-cyanoethyl ester (II) and ammonium formate in hot ethanol gives the protected racemic 1,4-dihydropyridine (III), which is submitted to a chiral preparative HPLC to obtain the (R)-(-)-enantiomer (IV). The deprotection of (IV) with aqueous methylamine affords (S)-(-)-2-[2-(2-aminoethoxy)ethoxymethyl]-4-(2,3-dichlorophenyl)-1,4-di hydropyridine-3,5-dicarboxylic acid 3-monoethyl ester (V). Finally, this compound is methylated with diazomethane in ethyl ether/methanol. The starting compound, the dichlorobenzylidene derivative (II) has been obtained as follows: The condensation of Meldrum's acid (X) with acetic acid (XII) by means of CDI and pyridine as before gives 5-acetyl-2,2-dimethyl-1,3-dioxane-4,6-dione (XIII), which is submitted to ring opening with 3-hydroxypropionitrile (XIV) in refluxing toluene yielding 2-cyanoethyl acetoacetate (XV). Finally, the condensation of (XV) with 2,3-dichlorobenzaldehyde (XVI) by means of piperidine and hexanoic acid in refluxing benzene affords the dichlorobenzylidene derivative (II) used as the second starting compound.
| 【1】 Dolle, F.; et al.; Highly efficient synthesis of [11C]S12968 and [11C]S12967, for the in vivo imaging of the cardiac calcium channels using PET. J Label Compd Radiopharm 2001, 44, 7, 481. |
| 【2】 Crouzel, C.; Duval, R.; Hinnen, F.; Fuseau, C.; Dollé, F.; Valette, H.; Péglion, J.-L.; Synthesis of two optically active calcium channel antagonists labelled with carbon-11 for in vivo cardiac PET imaging. Bioorg Med Chem 1997, 5, 4, 749. |
| 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) | 14743 | ethyl 4-[2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethoxy]ethoxy]-3-oxobutanoate | C18H21NO7 | 详情 | 详情 | |
| (II) | 14744 | 2-cyanoethyl (Z)-2-acetyl-3-(2,3-dichlorophenyl)-2-propenoate | C14H11Cl2NO3 | 详情 | 详情 | |
| (III) | 14745 | 5-(2-cyanoethyl) 3-ethyl 4-(2,3-dichlorophenyl)-2-([2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethoxy]ethoxy]methyl)-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate | C32H31Cl2N3O8 | 详情 | 详情 | |
| (IV) | 14746 | 5-(2-cyanoethyl) 3-ethyl (4S)-4-(2,3-dichlorophenyl)-2-([2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethoxy]ethoxy]methyl)-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate | C32H31Cl2N3O8 | 详情 | 详情 | |
| (V) | 14747 | (4R)-6-[[2-(2-aminoethoxy)ethoxy]methyl]-4-(2,3-dichlorophenyl)-5-(ethoxycarbonyl)-2-methyl-1,4-dihydro-3-pyridinecarboxylic acid | C21H26Cl2N2O6 | 详情 | 详情 | |
| (X) | 14738 | Meldrum's acid; 2,2-dimethyl-1,3-dioxane-4,6-dione；Malonic acid cyclic isopropylidene ester | 2033-24-1 | C6H8O4 | 详情 | 详情 |
| (XIII) | 12273 | 5-Acetyl-2,2-dimethyl-1,3-dioxane-4,6-dione | C8H10O5 | 详情 | 详情 | |
| (XIV) | 14029 | Ethylene cyanohydrin; ECN; 3-Hydroxypropanenitrile | 109-78-4 | C3H5NO | 详情 | 详情 |
| (XV) | 13993 | 2-cyanoethyl 3-oxobutanoate | C7H9NO3 | 详情 | 详情 | |
| (XVI) | 14742 | 2,3-dichlorobenzaldehyde | 6334-18-5 | C7H4Cl2O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The starting compound phthalimido derivative (I) could be obtained as follows: The condensation of 2-[2-(2-chloroethoxy)ethoxy]ethanol (VI) with potassium phthalimide (VII) in refluxing DMF gives the expected phthalimido derivative (VIII), which is oxidized with the Jones reagent in acetone yielding 2-[2-(2-phthalimidoethoxy)ethoxy]acetic acid (IX). The condensation of (IX) with 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid) (X) by means of carbonyldiimidazole (CDI) and pyridine in dichloromethane affords 2,2-dimethyl-5-[2-[2-(2-phthalimidoethoxy)ethoxy]acetyl]-1,3-dioxane-4,6-dione (XI), which is finally treated with refluxing ethanol to obtain the phthalimido derivative (I) used as starting material.
| 【1】 Crouzel, C.; Duval, R.; Hinnen, F.; Fuseau, C.; Dollé, F.; Valette, H.; Péglion, J.-L.; Synthesis of two optically active calcium channel antagonists labelled with carbon-11 for in vivo cardiac PET imaging. Bioorg Med Chem 1997, 5, 4, 749. |
| 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) | 14743 | ethyl 4-[2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethoxy]ethoxy]-3-oxobutanoate | C18H21NO7 | 详情 | 详情 | |
| (VI) | 14748 | 2-[2-(2-Chloroethoxy)ethoxy]-1-ethanol; 2-(2-(2-Chloroethoxy)ethoxy)ethanol | 5197-62-6 | C6H13ClO3 | 详情 | 详情 |
| (VII) | 10926 | (1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)potassium | C8H4KNO2 | 详情 | 详情 | |
| (VIII) | 14750 | 2-[2-[2-(2-Hydroxyethoxy)ethoxy]ethyl]-1H-isoindole-1,3(2H)-dione | C14H17NO5 | 详情 | 详情 | |
| (IX) | 14751 | 2-[2-[2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)ethoxy]ethoxy]acetic acid | C14H15NO6 | 详情 | 详情 | |
| (X) | 14738 | Meldrum's acid; 2,2-dimethyl-1,3-dioxane-4,6-dione；Malonic acid cyclic isopropylidene ester | 2033-24-1 | C6H8O4 | 详情 | 详情 |
| (XI) | 14752 | 2-(2-[2-[2-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-2-oxoethoxy]ethoxy]ethyl)-1H-isoindole-1,3(2H)-dione | C20H21NO9 | 详情 | 详情 |