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【结 构 式】 
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【分子编号】53201 【品名】ethyl 2-(2-bromo-1-oxo-2,3-dihydro-1H-inden-4-yl)acetate 【CA登记号】n/a |
【 分 子 式 】C13H13BrO3 【 分 子 量 】297.14842 【元素组成】C 52.55% H 4.41% Br 26.89% O 16.15% |
合成路线1
该中间体在本合成路线中的序号：(VII)Heck coupling of 2-bromophenylacetic acid (I) with acrylic acid (II) produces the dicarboxylic acid adduct (III). Subsequent catalytic hydrogenation of the olefinic double bond of (III) gives rise to the saturated diacid (IV). Then, Friedel-Crafts intramolecular cyclization of (IV) in hot H2SO4 affords indanone (V). Bromination of (V) in AcOH yields 2-bromo-1-oxoindan-4-ylacetic acid (VI). Esterification of (VI) is carried out via conversion to the corresponding acid chloride, followed by quenching with EtOH to provide the ethyl ester (VII). Condensation of bromo indanone (VII) with diethyl imidazole-2,4-dicarboxylate (VIII) furnishes the imidazolyl indanone (IX). Ring closure of keto ester (IX) with ammonium acetate in refluxing AcOH produces the tetracyclic compound (X). The ethyl ester groups of (X) are finally hydrolyzed under basic conditions to yield the title dicarboxylic acid.
| 【2】 Aloup, J.-C.; Bouquerel, J.; Damour, D.; Hardy, J.-C.; Jimonet, P.; Manfre, M.; Mignani, S.; Nemecek, P. (Aventis Pharma SA); 5H,10H-Imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one derivs., preparation thereof, intermediates thereof and drugs containing same. EP 0880522; FR 2743366; JP 2000505073; US 5990108; WO 9725328 . |
| 【1】 Mignani, S.; et al.; 9-Carboxymethyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one-2-carbocylic acid (RPR117824): Selective anticonvulsive and neuroprotective AMPA antagonist. Bioorg Med Chem 2002, 10, 5, 1627. |
| 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) | 62312 | 2-Bromophenylacetic acid; O-Bromophenylacetic Acid; o-BROMOPHENYLACETIC ACID; OBPAA | 18698-97-0 | C8H7BrO2 | 详情 | 详情 |
| (II) | 19139 | acrylic acid | 79-10-7 | C3H4O2 | 详情 | 详情 |
| (III) | 62313 | (Z)-3-[2-(2-hydroxy-2-oxoethyl)phenyl]-2-propenoic acid | C11H10O4 | 详情 | 详情 | |
| (IV) | 53198 | 3-[2-(carboxymethyl)phenyl]propanoic acid | n/a | C11H12O4 | 详情 | 详情 |
| (V) | 53199 | 2-(1-oxo-2,3-dihydro-1H-inden-4-yl)acetic acid | n/a | C11H10O3 | 详情 | 详情 |
| (VI) | 62314 | 2-(2-bromo-1-oxo-2,3-dihydro-1H-inden-4-yl)acetic acid | C11H9BrO3 | 详情 | 详情 | |
| (VII) | 53201 | ethyl 2-(2-bromo-1-oxo-2,3-dihydro-1H-inden-4-yl)acetate | n/a | C13H13BrO3 | 详情 | 详情 |
| (VIII) | 62315 | diethyl 1H-imidazole-2,4-dicarboxylate | C9H12N2O4 | 详情 | 详情 | |
| (IX) | 62316 | diethyl 1-[4-(2-ethoxy-2-oxoethyl)-1-oxo-2,3-dihydro-1H-inden-2-yl]-1H-imidazole-2,4-dicarboxylate | C22H24N2O7 | 详情 | 详情 | |
| (X) | 62317 | ethyl 9-(2-ethoxy-2-oxoethyl)-4-oxo-5,10-dihydro-4H-imidazo[1,2-a]indeno[1,2-e]pyrazine-2-carboxylate | C20H19N3O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)The cyclization of 3-[2-(carboxymethyl)phenyl]propionic acid (I) in the presence of conc. H2SO4 at 100 C gives 2-(1-oxoindan-4-yl)acetic acid (II), which is esterified with (COCl)2 and EtOH to yield the ethyl ester (III). The bromination of (III) with Br2 in HOAc affords 2-(2-bromo-1-oxoindan-4-yl)acetic acid ethyl ester (IV). The condensation of (IV) with 4-(diethoxyphosphoryl)-1H-imidazole-2-carboxylic acid ethyl ester (V) (obtained by cyclization of hydroxyamidinocarboxylic acid ethyl ester (VI) with ethynylphosphonic acid diethyl ester (VII) in the presence of TEA) provides the adduct (VIII). The cyclization of (VIII) with ammonium acetate in refluxing acetic acid gives the tetracyclic phosphonate (IX), which is finally hydrolyzed with refluxing aqueous HCl to yield the target phosphonic acid.
| 【1】 Boireau, A.; Böhme, G.A.; Canton, T.; et al.; RPR 119990, a novel alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid antagonist: Synthesis, pharmacological properties, and activity in an animal model of amyotrophic lateral sclerosis. J Pharmacol Exp Ther 2001, 299, 1, 314. |
| 【2】 Jimonet, P.; Bouquerel, J.; Bohme, G.A.; et al.; Bioisosteres of 9-carboxymethyl-4-oxo-imidazo[1,2-a]indeno-[1,2-e]pyrazin-2-carboxylic acid derivatives. Progress towards selective, potent in vivo AMPA antagonists wit longer durations of action. Bioorg Med Chem Lett 2001, 11, 2, 127. |
| 【3】 Aloup, J.-C.; Hardy, J.-C.; Mignani, S.; Jimonet, P.; Audiau, F.; Barreau, M.; Manfre, F.; Damour, D.; Ribeill, Y.; Genevois-Borella, A.; Nemecek, P. (Aventis Pharma SA); 5H-10H-Imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one derivs., preparation thereof, and drugs containing said derivs.. WO 9631511 . |
| 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) | 53198 | 3-[2-(carboxymethyl)phenyl]propanoic acid | n/a | C11H12O4 | 详情 | 详情 |
| (II) | 53199 | 2-(1-oxo-2,3-dihydro-1H-inden-4-yl)acetic acid | n/a | C11H10O3 | 详情 | 详情 |
| (III) | 53200 | ethyl 2-(1-oxo-2,3-dihydro-1H-inden-4-yl)acetate | n/a | C13H14O3 | 详情 | 详情 |
| (IV) | 53201 | ethyl 2-(2-bromo-1-oxo-2,3-dihydro-1H-inden-4-yl)acetate | n/a | C13H13BrO3 | 详情 | 详情 |
| (V) | 53202 | ethyl 4-(diethoxyphosphoryl)-1H-imidazole-2-carboxylate | n/a | C10H17N2O5P | 详情 | 详情 |
| (VI) | 53203 | ethyl 2-(hydroxyamino)-2-iminoacetate | n/a | C4H8N2O3 | 详情 | 详情 |
| (VII) | 53204 | diethyl ethynylphosphonate | n/a | C6H11O3P | 详情 | 详情 |
| (VIII) | 53205 | ethyl 4-(diethoxyphosphoryl)-1-[4-(2-ethoxy-2-oxoethyl)-1-oxo-2,3-dihydro-1H-inden-2-yl]-1H-imidazole-2-carboxylate | n/a | C23H29N2O8P | 详情 | 详情 |
| (IX) | 53206 | ethyl 2-[2-(diethoxyphosphoryl)-4-oxo-5,10-dihydro-4H-imidazo[1,2-a]indeno[1,2-e]pyrazin-9-yl]acetate | n/a | C21H24N3O6P | 详情 | 详情 |