【结 构 式】 |
【分子编号】41071 【品名】4-nitrophenyl (2S)-4-[(3aR,7aS)octahydro-2H-isoindol-2-yl]-2-benzyl-4-oxobutanoate 【CA登记号】 |
【 分 子 式 】C25H28N2O5 【 分 子 量 】436.5078 【元素组成】C 68.79% H 6.47% N 6.42% O 18.33% |
合成路线1
该中间体在本合成路线中的序号:(XXI)The optical resolution of racemic 2-benzylsuccinic acid (XV) using the chiral amines (R)-1-phenylethylamine (VII), (R)-1-(1-naphthyl)ethylamine (XIV) or (S)-1-phenyl-2-(4-tolyl)ethylamine (XVI) is carried out by fractional crystallization of the corresponding diastereomeric salts and treatment with 2N HCl, providing the desired enantiomer 2(S)-benzylsuccinic acid (XVII). Reaction of (XVII) with SOCl2 gives the corresponding acyl chloride (XVIII), which is treated with 4-nitrophenol (XIX) and TEA in dichloromethane to yield the activated diester (XX). The regioselective reaction of (XX) with cis-perhydroisoindole (V) in dichloromethane affords the monoamide (XXI), which by reaction with HCl and methanol provides the corresponding methyl ester (XXII). This ester is hydrolyzed with NaOH to the previously described chiral succinamic acid (XIII), which is finally converted into its calcium salt.
【1】 Castaner, R.M.; Sorbera, L.A.; Leeson, P.A.; Castaner, J.; Mitiglinide Calcium Hydrate. Drugs Fut 2000, 25, 10, 1034. |
【2】 Mukaiyama, Y.; Hokari, H.; Kamijo, T.; Yanagi, T.; Yamaguchi, T.; Yamamoto, I.; Preparation of optically active succinic acid derivatives. II. Efficient and practical synthesis of KAD-1229. Chem Pharm Bull 1998, 46, 2, 337-340. |
【3】 Yamaguchi, T.; et al.; Synthesis of KAD-1229, a succinic acid derivative with optical activity. 118th Annu Meet Pharmaceut Soc Jpn (March 31 1998, Kyoto) 1998, Abst 31(XP)9-9. |
【4】 Yamaguchi, T.; Kamijo, T.; Yanagi, T. (Kissei Pharmaceutical Co., Ltd.); Process for producing optically active benzylsuccinic acid and intermediate therefor. WO 9832727 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(V) | 41059 | (3aR,7aS)octahydro-1H-isoindole | C8H15N | 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 |
(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 |
(XV) | 41066 | 2-benzylsuccinic acid | C11H12O4 | 详情 | 详情 | |
(XVI) | 41067 | (1S)-2-(4-methylphenyl)-1-phenylethylamine; (1S)-2-(4-methylphenyl)-1-phenyl-1-ethanamine | 30339-30-1 | C15H17N | 详情 | 详情 |
(XVII) | 41068 | (2S)-2-benzylbutanedioic acid | C11H12O4 | 详情 | 详情 | |
(XVIII) | 41069 | (2S)-2-benzylbutanedioyl dichloride | C11H10Cl2O2 | 详情 | 详情 | |
(XIX) | 11236 | 4-Nitrophenol; p-Nitrophenol | 100-02-7 | C6H5NO3 | 详情 | 详情 |
(XX) | 41070 | bis(4-nitrophenyl) (2S)-2-benzylbutanedioate | C23H18N2O8 | 详情 | 详情 | |
(XXI) | 41071 | 4-nitrophenyl (2S)-4-[(3aR,7aS)octahydro-2H-isoindol-2-yl]-2-benzyl-4-oxobutanoate | C25H28N2O5 | 详情 | 详情 | |
(XXII) | 41072 | methyl (2S)-4-[(3aR,7aS)octahydro-2H-isoindol-2-yl]-2-benzyl-4-oxobutanoate | C20H27NO3 | 详情 | 详情 |