(2S)-2-(2-oxo-4-propylpyrrolidin-1-yl)butanoic acid -Drug Synthesis Database

【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 合成路线2

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 .

参考文献中间体

合成目标

【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) .

参考文献中间体

合成目标

【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