2-(2-Oxo-1-pyrrolidinyl)butyric acid -Drug Synthesis Database

【结构式】

【分子编号】11268

【品名】2-(2-Oxo-1-pyrrolidinyl)butyric acid

【CA登记号】67118-31-4

【分子式】C₈H₁₃NO₃

【分子量】171.19616

【元素组成】C 56.13% H 7.65% N 8.18% O 28.04%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(VII)

An alternative procedure involves hydrolysis of racemic ethyl 2-(2-oxopyrrolidin-1-yl)burytate (VI) with sodium hydroxide to give racemic 2-(2-oxopyrrolidin-1-yl)butyric acid (VII), which is resolved by fractional crystallization with (R)-(+)-alpha-methylbenzylamine in benzene, followed by acid-base treatment to give (S)-2-(2-oxopyrrolidin-1-yl)butyric acid (VIII). Compound (VIII) is finally treated with ethyl chloroformiate and ammonia in dichloromethane.

参考文献中间体

合成目标

【1】 Cossement, E.; Motte, G.; Geerts, J.-P.; Gobert, J. (UCB SA); The preparation of S-alpha-ethyl-2-oxo-1-pyrrolidineacetamide. GB 2225322 .
【2】 Castaner, J.; Prous, J.; Mealy, N.; Levetiracetam. Drugs Fut 1994, 19, 2, 111.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	10039	(1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine	3886-69-9	C₈H₁₁N	详情	详情
(VI)	11267	ethyl 2-(2-oxo-1-pyrrolidinyl)butanoate		C₁₀H₁₇NO₃	详情	详情
(VII)	11268	2-(2-Oxo-1-pyrrolidinyl)butyric acid	67118-31-4	C₈H₁₃NO₃	详情	详情
(VIII)	11269	(2S)-2-(2-Oxo-1-pyrrolidinyl)butyric acid	102849-49-0	C₈H₁₃NO₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IV)

The condensation of 2-pyrrolidone (I) with ethyl 2-bromobutyrate (II) by means of NaOEt in ethanol gives 2-(2-oxopyrrolidin-1-yl)butyric acid ethyl ester (III), which is hydrolyzed with NaOH to the corresponding acid (IV). The reaction of (IV) with SOCl2 affords the acyl chloride (V), which is treated with ammonia to provide the expected amide (VI). Alternatively, the reaction of acid (IV) with ammonia and thermolysis of the resulting ammonium salt also gives the butyramide (VI). Finally, the optical resolution of the racemic amide (VI) is performed by chiral HPLC.

参考文献中间体

合成目标

【1】 Gobert, J.; Geerts, J.-P.; Bodson, G. (UCB SA); (S)-alpha-Ethyl-2-oxopyrrolidineacetamide. AU 8542530; EP 0162036; ES 8608485; ES 8704893; US 4696943; US 4837223 .
【2】 Strubbe, J.H.L.; Linz, R.A. (UCB SA); New N-substd. lactams. DE 2106418 .
【3】 Cavoy, E.; Hamende, M.; Deleers, M.; Canvat, J.-P.; Zimmermann, V.; Futagawa, T. (Daicel Chemical Industries, Ltd.; UCB SA); Process for the preparation of levetiracetam. US 6107492 .
【4】 Cavoy, E.; Hamende, M.; Deleers, M.; Canvat, J.-P.; Zimmermann, V. (UCB SA); Process for preparing (S)- and (R)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide. US 6124473 .

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)	27397	2-Pyrrolidinone	616-45-5	C₄H₇NO	详情	详情
(II)	61962	DL-Ethyl 2-bromobutyrate; Ethyl 2-bromobutyrate; Ethyl 2-Bromobutyrate; DL-Ethyl-(2-brombutyrat); 2-Bromo-n-butyric Acid Ethyl Ester; Ethyl 2-Bromo-n-butyrate; 2-Bromobutyric acid ethyl ester; Ethyl-2-bromobutyrate; BNBE; alpha-Bromobutyric acid ethyl ester	533-68-6	C₆H₁₁BrO₂	详情	详情
(III)	61963	ethyl 2-(2-oxo-1-pyrrolidinyl)butanoate		C₁₀H₁₇NO₃	详情	详情
(IV)	11268	2-(2-Oxo-1-pyrrolidinyl)butyric acid	67118-31-4	C₈H₁₃NO₃	详情	详情
(V)	61964	2-(2-oxo-1-pyrrolidinyl)butanoyl chloride		C₈H₁₂ClNO₂	详情	详情
(VI)	61965	2-(2-oxo-1-pyrrolidinyl)butanamide		C₈H₁₄N₂O₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VII)-rac

Reaction of (S)-2-aminobutyramide (I) with ethyl 4-bromobutyrate (II) in the presence of triethylamine in toluene gives ethyl (S)-4-[1-(carbamoyl)propylamino]butyrate (III), which is cyclized in toluene by means of 2-hydroxypyridine. Compound (I) can also be condensed with 4-chlorobutyryl chloride (IV) either directly in the presence of tetrabutylammonium bromide (TBAB) in dichloromethane, followed by in situ treatment with potassium hydroxide, or via the isolation of intermediate (S)-N-[1-(carbamoyl)propyl]-4-chlorobutyramide (V). An alternative procedure involves hydrolysis of racemic ethyl 2-(2-oxopyrrolidin-1-yl)butyrate (VI) with sodium hydroxide to give racemic 2-(2-oxopyrrolidin-1-yl)butyric acid (VII), which is resolved by fractional crystallization with (R)-(+)-alpha-methylbenzylamine in benzene, followed by acid-base treatment to give (S)-2-(2-oxopyrrolidin-1-yl)butyric acid (VIII). Compound (VIII) is finally treated with ethyl chloroformiate and ammonia in dichloromethane. A third procedure involves Ni-Raney desulfurization of (S)-4-(methylthio)-2-(2-oxopyrrolidin-1-yl)butyramide (XI), prepared from (S)-2-amino-4-(methylthio)butyramide (IX) by reaction with 4-chlorobutyryl chloride (IV). Compound (XI) can also be obtained by treatment of (IX) with ethyl 4-bromobutyrate (II) to give ethyl (S)-4-[1-(carbamoyl)-3-(methylthio)propylamino]butyrate (X), which is cyclized in toluene by means of 2-hydroxypyridine.

参考文献中间体

合成目标

【1】 Gobert, J.; Geerts, J.-P.; Bodson, G. (UCB SA); (S)-alpha-Ethyl-2-oxopyrrolidineacetamide. AU 8542530; EP 0162036; ES 8608485; ES 8704893; US 4696943; US 4837223 .
【2】 Cossement, E.; Motte, G.; Geerts, J.-P.; Gobert, J. (UCB SA); The preparation of S-alpha-ethyl-2-oxo-1-pyrrolidineacetamide. GB 2225322 .
【3】 Castaner, J.; Prous, J.; Mealy, N.; Levetiracetam. Drugs Fut 1994, 19, 2, 111.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	10039	(1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine	3886-69-9	C₈H₁₁N	详情	详情
(VII)-rac	11268	2-(2-Oxo-1-pyrrolidinyl)butyric acid	67118-31-4	C₈H₁₃NO₃	详情	详情
(I)	11262	(2S)-2-Aminobutanamide		C₄H₁₀N₂O	详情	详情
(II)	11263	ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate	2969-81-5	C₆H₁₁BrO₂	详情	详情
(III)	11264	ethyl 4-[[(1S)-1-(aminocarbonyl)propyl]amino]butanoate		C₁₀H₂₀N₂O₃	详情	详情
(IV)	11265	4-Chlorobutanoyl chloride; 4-Chlorobutyric acid chloride	4635-59-0	C₄H₆Cl₂O	详情	详情
(V)	11266	(2S)-2-[(4-Chlorobutanoyl)amino]butanamide		C₈H₁₅ClN₂O₂	详情	详情
(VI)	11267	ethyl 2-(2-oxo-1-pyrrolidinyl)butanoate		C₁₀H₁₇NO₃	详情	详情
(VIII)	11269	(2S)-2-(2-Oxo-1-pyrrolidinyl)butyric acid	102849-49-0	C₈H₁₃NO₃	详情	详情
(IX)	11270	(2S)-2-Amino-4-(methylsulfanyl)butanamide		C₅H₁₂N₂OS	详情	详情
(X)	11271	ethyl 4-[[(1S)-1-(aminocarbonyl)-3-(methylsulfanyl)propyl]amino]butanoate		C₁₁H₂₂N₂O₃S	详情	详情
(XI)	11272	(2S)-4-(Methylsulfanyl)-2-(2-oxo-1-pyrrolidinyl)butanamide		C₉H₁₆N₂O₂S	详情	详情

Extended Information