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【结 构 式】 
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【分子编号】41074 【品名】benzyl (2S)-4-[(3aR,7aS)octahydro-2H-isoindol-2-yl]-2-benzyl-4-oxobutanoate 【CA登记号】 |
【 分 子 式 】C26H31NO3 【 分 子 量 】405.53708 【元素组成】C 77.01% H 7.7% N 3.45% O 11.84% |
合成路线1
该中间体在本合成路线中的序号：(XXIV)The reaction of 2(S)-benzylsuccinic acid 1-benzyl monoester (XXIII) with cis-perhydroisoindole (V) by means of isobutyl chloroformate and NMM in THF gives the succinamic ester (XXIV), which is hydrogenated with H2 over Pd/C in ethanol, yielding the already described succinamic acid (XIII). Finally, this compound is 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】 Sato, F.; Tsubaki, A.; Hokari, H.; Tanaka, N.; Saito, M.; Akahane, K.; Kobayashi, M. (Kissei Pharmaceutical Co., Ltd.); Succinic acid cpds.. EP 0507534; JP 1992330055; JP 1992356459; JP 1993230019; US 5202335 . |
| 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 | |
| (XIII) | 41064 | (2S)-4-[(3aR,7aS)octahydro-2H-isoindol-2-yl]-2-benzyl-4-oxobutyric acid | C19H25NO3 | 详情 | 详情 | |
| (XXIII) | 41073 | (3S)-3-benzyl-4-(benzyloxy)-4-oxobutyric acid | C18H18O4 | 详情 | 详情 | |
| (XXIV) | 41074 | benzyl (2S)-4-[(3aR,7aS)octahydro-2H-isoindol-2-yl]-2-benzyl-4-oxobutanoate | C26H31NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXIV)The condensation of 2(S)-benzylsuccinic acid (XVII) with cis-perhydroisoindole (V) by means of imidazole, SOCl2 and TEA in ethyl acetate gives the succinamic acid (XIII), which is esterified with benzyl bromide (XXV) and K2CO3 in ethyl acetate or with benzyl alcohol (XXVI) and DCC in the same solvent, yielding the succinamic ester (XXIV). Finally, this compound is treated with NaOH or with H2 over Pd/C and reacted with CaCl2, yielding high purity mitiglinide calcium. The one-pot sequential reaction of imidazole with SOCl2, 2(S)-benzylsuccinic acid (XVII) and cis-perhydroisoindole (V), followed by hydrolysis with HCl, gives succinamic acid (XIII), which is finally treated with 2N NaOH and CaCl2.
| 【1】 Castaner, R.M.; Sorbera, L.A.; Leeson, P.A.; Castaner, J.; Mitiglinide Calcium Hydrate. Drugs Fut 2000, 25, 10, 1034. |
| 【2】 Yamaguchi, T.; Yanagi, T.; Yamamoto, I.; Mukaiyama, Y.; Kamijo, T.; Hokari, H.; Preparation of optically active succinic acid derivatives. III. Regioselective condensation reactions of optically active 2-substituted succinic acids with diimidazolide. Yakugaku Zasshi 1998, 118, 6, 248-255. |
| 【3】 Yamaguchi, T.; et al.; Synthesis of KAD-1229, a succinic acid derivative with optical activity (1). 118th Annu Meet Pharmaceut Soc Jpn (March 31 1998, Kyoto) 1998, Abst 01(XD)13-1. |
| 【4】 Yanagi, T.; Kamijo, T.; Yamaguchi, T. (Kissei Pharmaceutical Co., Ltd.); Process for producing benzylsuccinic acid derivs.. EP 0967204; WO 9832736 . |
| 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 | |
| (XIII) | 41064 | (2S)-4-[(3aR,7aS)octahydro-2H-isoindol-2-yl]-2-benzyl-4-oxobutyric acid | C19H25NO3 | 详情 | 详情 | |
| (XVII) | 41068 | (2S)-2-benzylbutanedioic acid | C11H12O4 | 详情 | 详情 | |
| (XXIV) | 41074 | benzyl (2S)-4-[(3aR,7aS)octahydro-2H-isoindol-2-yl]-2-benzyl-4-oxobutanoate | C26H31NO3 | 详情 | 详情 | |
| (XXV) | 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 |
| (XXVI) | 18710 | Benzyl alcohol; Phenylmethanol | 100-51-6 | C7H8O | 详情 | 详情 |