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【结 构 式】

【分子编号】69032

【品名】(2S)-2-(2-oxo-4-propylpyrrolidin-1-yl)butanoic acid

【CA登记号】 

【 分 子 式 】C11H19NO3

【 分 子 量 】213.2768

【元素组成】C 61.95% H 8.98% N 6.57% O 22.51%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(IX)

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

合成路线2

该中间体在本合成路线中的序号:(IX)

Conjugate addition of nitromethane to 2-hexenoic acid ethyl ester (XXVII) by means of DBU gives ethyl 2-(nitromethyl)hexanoate (XXVIII), which by nitro group reduction with H2 and Raney-Ni in MeOH at 55 °C cyclizes to the racemic lactam (XXIX). Resolution of compound (XXIX) using chiral column chromatography results in the optically pure (R)-enantiomer (X) .
The intermediate pyrrolidinone butyric acid (IX) can be obtained by N-alkylation of 4-propyl-2-pyrrolidinone (XXIX) with (R)-2-bromobutyric acid (XXX) in the presence of NaH in THF .
In an alternative procedure, alkylation of ethyl 4-amino-3-propylbutyrate hydrochloride (XXXI) with methyl (R)-2-bromobutyrate (XXXII) by means of K2CO3 in acetonitrile gives the amino diester (XXXIII), which cyclizes to the pyrrolidinone (XXXIV) by heating in toluene at 80 °C in the presence of a catalytic amount of 2-hydroxypyridine. Finally, saponification of methyl ester (XXXIV) using aqueous NaOH then affords the corresponding carboxylic acid (IX) .

1 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.
2 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
(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
(XXVII) 69045 2-hexenoic acid ethyl ester;trans-2-hexenoic acid ethyl ester;ethyl (E)-hex-2-enoate 27829-72-7 C8H14O2 详情 详情
(XXVIII) 69046 ethyl 3-(nitromethyl)hexanoate   C9H17NO4 详情 详情
(XXIX) 69047 4-propylpyrrolidin-2-one   C7H13NO 详情 详情
(XXX) 69048 (R)-2-bromobutyric acid;(R)-2-Bromobutyricacid;D-2-Bromobutanoic acid 2681-94-9 C4H7BrO2 详情 详情
(XXXI) 69049 ethyl 4-amino-3-propylbutyrate hydrochloride;ethyl 3-(aminomethyl)hexanoate hydrochloride   C9H19NO2.HCl 详情 详情
(XXXII) 69050 methyl (R)-2-bromobutyrate   C5H9BrO2 详情 详情
(XXXIII) 69051 methyl 3-((((R)-1-methoxy-1-oxobutan-2-yl)amino)methyl)hexanoate   C13H25NO4 详情 详情
(XXXIV) 69052 (2R)-methyl 2-(2-oxo-4-propylpyrrolidin-1-yl)butanoate   C12H21NO3 详情 详情
Extended Information