【结 构 式】 |
【分子编号】41062 【品名】4-[(3aR,7aS)octahydro-2H-isoindol-2-yl]-2-benzyl-4-oxobutyric acid 【CA登记号】 |
【 分 子 式 】C19H25NO3 【 分 子 量 】315.41244 【元素组成】C 72.35% H 7.99% N 4.44% O 15.22% |
合成路线1
该中间体在本合成路线中的序号:(X)The condensation of diethyl succinate (IX) with benzaldehyde (II) gives 2-benzylidenesuccinic acid (III), which is treated with refluxing Ac2O to yield the corresponding anhydride (IV). Reaction of (IV) with cis-perhydroisoindole (V) in toluene affords the monoamide (VI), which is reduced with H2 over Pd/C in ethanol to provide the racemic benzylsuccinamic acid (X). Esterification of (X) with (S)-N-benzylmandelamide (XI) by means of DCC and DMAP in dichloromethane gives a mixture of diastereomeric esters, which were separated by column chromatography on silica gel to provide the desired diastereomer (XII). The hydrolysis of (XII) with NaOH in methanol yields the chiral acid (XIII), which is finally treated first with NaOH and then with CaCl2 in water. The preceding optical resolution of racemic acid (X) can also be performed with (R)-1-phenylethylamine (VII) or (R)-1-(1-naphthyl)ethylamine (XIV) by fractional crystallization of the corresponding diastereomeric salts and treatment with 2N HCl.
【1】 Castaner, R.M.; Sorbera, L.A.; Leeson, P.A.; Castaner, J.; Mitiglinide Calcium Hydrate. Drugs Fut 2000, 25, 10, 1034. |
【2】 Yamaguchi, T.; et al.; Preparation of optically active succinic acid derivatives. I. Optical resolution of 2-benzyl-3-(cis-hexahydroisoindolin-2-ylcarbonyl)propionic acid. Chem Pharm Bull 1997, 45, 9, 1518. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(II) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
(III) | 41057 | 2-[(Z)-benzylidene]succinic acid | C11H10O4 | 详情 | 详情 | |
(IV) | 41058 | 3-[(Z)-benzylidene]-2,5(4H)-furandione | C11H8O3 | 详情 | 详情 | |
(V) | 41059 | (3aR,7aS)octahydro-1H-isoindole | C8H15N | 详情 | 详情 | |
(VI) | 41060 | (Z)-2-[2-[(3aR,7aS)octahydro-2H-isoindol-2-yl]-2-oxoethyl]-3-phenyl-2-propenoic acid | C19H23NO3 | 详情 | 详情 | |
(VII) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
(IX) | 12313 | diethyl succinate | 123-25-1 | C8H14O4 | 详情 | 详情 |
(X) | 41062 | 4-[(3aR,7aS)octahydro-2H-isoindol-2-yl]-2-benzyl-4-oxobutyric acid | C19H25NO3 | 详情 | 详情 | |
(XI) | 41063 | (2S)-N-benzyl-2-hydroxy-2-phenylethanamide | C15H15NO2 | 详情 | 详情 | |
(XII) | 41065 | (1S)-2-(benzylamino)-2-oxo-1-phenylethyl (2S)-4-[(3aR,7aS)octahydro-2H-isoindol-2-yl]-2-benzyl-4-oxobutanoate | C34H38N2O4 | 详情 | 详情 | |
(XIII) | 41064 | (2S)-4-[(3aR,7aS)octahydro-2H-isoindol-2-yl]-2-benzyl-4-oxobutyric acid | C19H25NO3 | 详情 | 详情 | |
(XIV) | 17443 | (1R)-1-(1-naphthyl)ethylamine; (1R)-1-(1-naphthyl)-1-ethanamine | 3886-70-2 | C12H13N | 详情 | 详情 |