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【结 构 式】

【分子编号】41064

【品名】(2S)-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%

与该中间体有关的原料药合成路线共 4 条

合成路线1

该中间体在本合成路线中的序号:(XIII)

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

合成路线2

该中间体在本合成路线中的序号:(XIII)

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

合成路线3

该中间体在本合成路线中的序号:(XIII)

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4

该中间体在本合成路线中的序号:(XIII)

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
Extended Information