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【结 构 式】 
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【分子编号】58392 【品名】(2R)-2-(2-oxo-4-propyl-2,5-dihydro-1H-pyrrol-1-yl)butanamide 【CA登记号】 |
【 分 子 式 】C11H18N2O2 【 分 子 量 】210.2762 【元素组成】C 62.83% H 8.63% N 13.32% O 15.22% |
合成路线1
该中间体在本合成路线中的序号：(III)Reductive amination of 5-hydroxy-4-propyl-2-furanone (I) with (S)-2-aminobutyramide (II) in the presence of NaBH4 yields the dihydropyrrolone (III). Transfer hydrogenation of (III) with ammonium formate and Pd/C provides a diastereoisomeric mixture of pyrrolidinones, from which the title compound is isolated by preparative HPLC on chiral phase.
| 【1】 Michel, P.; Differding, E.; Pasau, P.; Kenda, B.; Lallemand, B.; Matagne, A.; Talaga, P. (UCB SA); 2-Oxo-1-pyrrolidine derivs., processes for preparing them and their uses. WO 0162726; WO 0164637 . |
合成路线2
该中间体在本合成路线中的序号：(VI)Condensation of 2(S)-aminobutyramide (I) with Meldrum’s acid derivative (II) in refluxing acetonitrile affords a mixture of two pyrrolidonecarboxylic acid regioisomers, (III) and (IV), which, without isolation, are subjected to decarboxylation in methyl isobutyl ketone at 120 °C, and then separated by column chromatography .
Alternatively, 2(S)-aminobutyramide (I) –obtained by basification of either its tartrate salt with NH4OH/i-PrOH or its hydrochloride salt with NH3/i-PrOH (2)– is reductively condensed with 5-hydroxy-4-propyl-2-furanone (V) by means of NaBH4 and NaOH in H2O/toluene, yielding the dihydropyrrol-2-one (VI) . Transfer hydrogenation of compound (VI) with ammonium formate and Pd/C in H2O at 50 °C provides the diastereomeric mixture of pyrrolidinones (VII) , which are finally separated by column chromatography or recrystallization .
The intermediate dihydropyrrolone (VII) is alternatively obtained by direct condensation of furanone (V) with 2(S)-aminobutyramide (I) in the presence of H2 and Pd/C in AcOH/i-PrOH or by cyclization of aminoamide (I) with 3-(iodomethyl)hexanoyl chloride (VIII) by means of KOH and tetrabutylammonium bromide in CH2Cl2 .
Amide (VII) is also prepared from 2-(2-oxo-4-propylpyrrolidino)-butyric acid (IX) via activation as the corresponding mixed anhydride with ethyl chloroformate and Et3N in THF, followed by quenching with liquid ammonia .
Similarly, alkylation of optically pure 4(R)-propyl-2-pyrrolidinone (X) with racemic methyl 2-bromobutyrate (XI) in the presence of NaH in THF affords pyrrolidinone butyrate methyl ester (XII) as a diastereomeric mixture. Subsequent ammonolysis of ester (XII) with aqueous ammonia gives the corresponding mixture of amides (XIII) separated using column chromatography .
| 【1】 Ates, C., Schule, A. (UCB SA). 3-Carboxy-2-oxo-1-pyrrolidine derivatives and their uses. EP 1993998, JP 2009518335, US 2009012313, WO 2007065634. |
| 【2】 Surtees, J., Lurquin, F., Diouf, O. (UCB SA). Process for preparing 2-oxo-1-pyrrolidine derivatives. CA 2538938, EP 1667967, JP 2007515387, US 2007100150, US 7629474, WO 2005028435. |
| 【3】 Kenda, B., Matagne, A., Michel, P., Pasau, P., Differding, E., Lallemand, B., Talaga, P. (UCB SA). 2-Oxo-1-pyrrolidine derivatives, processes for preparing them and their uses. EP 1447399, EP 1452524, EP 1604979, JP 2003523996, JP 2003528828, JP 2006022107, JP 2007182459, US 200312000, US 2004116507, US 2005171187, US 2005171188, US 2005159475, US 2008097109, US 6784197, US 6806287, US 6911461, US 7358276, WO 2001062726, WO 2001064637. |
| 【4】 Kenda, B.M., Matagne, A.C., Talaga, P.E. et al. Discovery of 4-substituted pyrrolidone butanamides as new agents with significant antiepileptic activity. J Med Chem 2004, 47(3): 530-49. |
| 【5】 Surtees, J., Bouvy, D., Thomas, A., Combret, Y., Frank, M., Schmidt, G. (UCB SA). Process for the preparation of 2-oxo-1-pyrrolidine derivatives. EP 1806339. |
| 【6】 Ates, C., Lurquin, F., Quesnel, Y., Schule, A. (UCB SA). 4-Substituted pyrrolidin-2-ones and their use. EP 1926710, JP 2009507870, US 2009318708, WO 2007031263. |
| 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) | 11262 | (2S)-2-Aminobutanamide | C4H10N2O | 详情 | 详情 | |
| (II) | 69027 | (R)-6,6-dimethyl-1-propyl-5,7-dioxaspiro[2.5]octane-4,8-dione | C11H16O4 | 详情 | 详情 | |
| (III) | 69028 | (4R)-1-((R)-1-amino-1-oxobutan-2-yl)-2-oxo-4-propylpyrrolidine-3-carboxylic acid | C12H20N2O4 | 详情 | 详情 | |
| (IV) | 69029 | 1-((R)-1-amino-1-oxobutan-2-yl)-2-oxo-5-propylpyrrolidine-3-carboxylic acid | C12H20N2O4 | 详情 | 详情 | |
| (V) | 58391 | 5-hydroxy-4-propyl-2(5H)-furanone；5-hydroxy-4-propyl-2-furanone | 78920-10-2 | C7H10O3 | 详情 | 详情 |
| (VI) | 58392 | (2R)-2-(2-oxo-4-propyl-2,5-dihydro-1H-pyrrol-1-yl)butanamide | C11H18N2O2 | 详情 | 详情 | |
| (VII) | 69030 | (2R)-2-(2-oxo-4-propylpyrrolidin-1-yl)butanamide | C11H20N2O2 | 详情 | 详情 | |
| (VIII) | 69031 | 3-(iodomethyl)hexanoyl chloride | C7H12ClIO | 详情 | 详情 | |
| (IX) | 69032 | (2S)-2-(2-oxo-4-propylpyrrolidin-1-yl)butanoic acid | C11H19NO3 | 详情 | 详情 | |
| (X) | 69034 | 4(R)-propyl-2-pyrrolidinone | C7H13NO | 详情 | 详情 | |
| (XI) | 69033 | methyl 2-bromobutyrate;2-Bromobutyric acid methyl ester | 3196-15-4 | C5H9BrO2 | 详情 | 详情 |
| (XII) | 69035 | methyl 2-((R)-2-oxo-4-propylpyrrolidin-1-yl)butanoate | C12H21NO3 | 详情 | 详情 | |
| (XIII) | 69036 | 2-((R)-2-oxo-4-propylpyrrolidin-1-yl)butanamide | C11H20N2O2 | 详情 | 详情 |