tert-butyl 2-oxo-1-pyrrolidinecarboxylate -Drug Synthesis Database

【结构式】

【分子编号】40014

【品名】tert-butyl 2-oxo-1-pyrrolidinecarboxylate

【CA登记号】

【分子式】C₉H₁₅NO₃

【分子量】185.22304

【元素组成】C 58.36% H 8.16% N 7.56% O 25.91%

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：(II)

2-Pyrrolidinone (I) was protected as the N-Boc derivative (II) and then alkylated with 3-bromo-2-methylpropene (III) in the presence of LDA to yield (IV). Further alkylation of (IV) with tert-butyl bromoacetate gave the dialkylated pyrrolidinone (V). Catalytic hydrogenation of the 2-methylpropenyl substituent of (V) produced the racemic isobutyl analogue (VI), which was resolved by means of chiral HPLC. The desired (S)-enantiomer (VII) was deprotected by treatment with magnesium ethoxide, affording pyrrolidinone (VIII). N-Alkylation of the pyrrolidinone (VIII) with triflate (IX) furnished adduct (X), which was hydrolyzed to carboxylic acid (XI) with methanolic NaOH. After activation of (XI) with carbonyl diimidazole, coupling with methylamine gave rise to amide (XII). Cleavage of the tert-butyl ester group of (XII) employing trifluoroacetic acid produced carboxylic acid (XIII). This was finally coupled with hydroxylamine using EDC and HOBt.

参考文献中间体

合成目标

【1】 Jacobsen, E.J. (Pharmacia & Upjohn AB); Hydroxamic acid derivs. for use with the treatment of diseases related to connective tissue degradation. EP 0898562; JP 2000506163; US 5712300; WO 9732846 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	11021	Methanamine; Methylamine	74-89-5	CH₅N	详情	详情
	17430	2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate	5292-43-3	C₆H₁₁BrO₂	详情	详情
(I)	27397	2-Pyrrolidinone	616-45-5	C₄H₇NO	详情	详情
(II)	40014	tert-butyl 2-oxo-1-pyrrolidinecarboxylate		C₉H₁₅NO₃	详情	详情
(III)	40015	3-bromo-2-methyl-1-propene	1458-98-6	C₄H₇Br	详情	详情
(IV)	40016	tert-butyl 3-(2-methyl-2-propenyl)-2-oxo-1-pyrrolidinecarboxylate		C₁₃H₂₁NO₃	详情	详情
(V)	40017	tert-butyl 3-[2-(tert-butoxy)-2-oxoethyl]-3-(2-methyl-2-propenyl)-2-oxo-1-pyrrolidinecarboxylate		C₁₉H₃₁NO₅	详情	详情
(VI)	40018	tert-butyl 3-[2-(tert-butoxy)-2-oxoethyl]-3-isobutyl-2-oxo-1-pyrrolidinecarboxylate		C₁₉H₃₃NO₅	详情	详情
(VII)	40019	tert-butyl (3S)-3-[2-(tert-butoxy)-2-oxoethyl]-3-isobutyl-2-oxo-1-pyrrolidinecarboxylate		C₁₉H₃₃NO₅	详情	详情
(VIII)	40020	tert-butyl 2-[(3S)-3-isobutyl-2-oxopyrrolidinyl]acetate		C₁₄H₂₅NO₃	详情	详情
(IX)	40025	methyl (2R)-2-cyclohexyl-2-[[(trifluoromethyl)sulfonyl]oxy]ethanoate		C₁₀H₁₅F₃O₅S	详情	详情
(X)	40021	methyl (2S)-2-[(3S)-3-[2-(tert-butoxy)-2-oxoethyl]-3-isobutyl-2-oxopyrrolidinyl]-2-cyclohexylethanoate		C₂₃H₃₉NO₅	详情	详情
(XI)	40022	(2S)-2-[(3S)-3-[2-(tert-butoxy)-2-oxoethyl]-3-isobutyl-2-oxopyrrolidinyl]-2-cyclohexylethanoic acid		C₂₂H₃₇NO₅	详情	详情
(XII)	40023	tert-butyl 2-[(3S)-1-[(1S)-1-cyclohexyl-2-(methylamino)-2-oxoethyl]-3-isobutyl-2-oxopyrrolidinyl]acetate		C₂₃H₄₀N₂O₄	详情	详情
(XIII)	40024	2-[(3S)-1-[(1S)-1-cyclohexyl-2-(methylamino)-2-oxoethyl]-3-isobutyl-2-oxopyrrolidinyl]acetic acid		C₁₉H₃₂N₂O₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

2-Pyrrolidinone (I) was protected as the N-Boc derivative (II) and then alkylated with 3-bromo-2-methylpropene (III) in the presence of LDA to yield (IV). Further alkylation of (IV) with tert-butyl bromoacetate gave the dialkylated pyrrolidinone (V). Catalytic hydrogenation of the 2-methylpropenyl substituent of (V) produced the racemic isobutyl analogue (VI), which was resolved by means of chiral HPLC. The desired (S)-enantiomer (VII) was deprotected by treatment with magnesium ethoxide, affording pyrrolidinone (VIII). Triflate (XI) was obtained from D-phenyllactic acid (IX) by formation of the methyl ester (X) upon treatment with iodomethane, followed by reaction with trifluoromethanesulfonic anhydride and pyridine. N-Alkylation of the pyrrolidinone (VIII) with triflate (XI) furnished adduct (XII), which was hydrolyzed to carboxylic acid (XIII) with methanolic NaOH. After activation of (XIII) with carbonyl diimidazole, coupling with methylamine gave rise to amide (XIV). Cleavage of the tert-butyl ester group of (XIV) employing trifluoroacetic acid produced carboxylic acid (XV). This was finally coupled with hydroxylamine using EDC and HOBt.

参考文献中间体

合成目标

【1】 Jacobsen, E.J. (Pharmacia & Upjohn AB); Hydroxamic acid derivs. for use with the treatment of diseases related to connective tissue degradation. EP 0898562; JP 2000506163; US 5712300; WO 9732846 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	11021	Methanamine; Methylamine	74-89-5	CH₅N	详情	详情
	17430	2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate	5292-43-3	C₆H₁₁BrO₂	详情	详情
(I)	27397	2-Pyrrolidinone	616-45-5	C₄H₇NO	详情	详情
(II)	40014	tert-butyl 2-oxo-1-pyrrolidinecarboxylate		C₉H₁₅NO₃	详情	详情
(III)	40015	3-bromo-2-methyl-1-propene	1458-98-6	C₄H₇Br	详情	详情
(IV)	40016	tert-butyl 3-(2-methyl-2-propenyl)-2-oxo-1-pyrrolidinecarboxylate		C₁₃H₂₁NO₃	详情	详情
(V)	40017	tert-butyl 3-[2-(tert-butoxy)-2-oxoethyl]-3-(2-methyl-2-propenyl)-2-oxo-1-pyrrolidinecarboxylate		C₁₉H₃₁NO₅	详情	详情
(VI)	40018	tert-butyl 3-[2-(tert-butoxy)-2-oxoethyl]-3-isobutyl-2-oxo-1-pyrrolidinecarboxylate		C₁₉H₃₃NO₅	详情	详情
(VII)	40019	tert-butyl (3S)-3-[2-(tert-butoxy)-2-oxoethyl]-3-isobutyl-2-oxo-1-pyrrolidinecarboxylate		C₁₉H₃₃NO₅	详情	详情
(VIII)	40020	tert-butyl 2-[(3S)-3-isobutyl-2-oxopyrrolidinyl]acetate		C₁₄H₂₅NO₃	详情	详情
(IX)	40026	(2R)-2-hydroxy-3-phenylpropionic acid	7326-19-4	C₉H₁₀O₃	详情	详情
(X)	13878	methyl (2R)-2-hydroxy-3-phenylpropanoate		C₁₀H₁₂O₃	详情	详情
(XI)	40027	methyl (2R)-3-phenyl-2-[[(trifluoromethyl)sulfonyl]oxy]propanoate		C₁₁H₁₁F₃O₅S	详情	详情
(XII)	40028	methyl (2S)-2-[(3S)-3-[2-(tert-butoxy)-2-oxoethyl]-3-isobutyl-2-oxopyrrolidinyl]-3-phenylpropanoate		C₂₄H₃₅NO₅	详情	详情
(XIII)	40029	(2S)-2-[(3S)-3-[2-(tert-butoxy)-2-oxoethyl]-3-isobutyl-2-oxopyrrolidinyl]-3-phenylpropionic acid		C₂₃H₃₃NO₅	详情	详情
(XIV)	40030	tert-butyl 2-[(3S)-1-[(1S)-1-benzyl-2-(methylamino)-2-oxoethyl]-3-isobutyl-2-oxopyrrolidinyl]acetate		C₂₄H₃₆N₂O₄	详情	详情
(XV)	40031	2-[(3S)-1-[(1S)-1-benzyl-2-(methylamino)-2-oxoethyl]-3-isobutyl-2-oxopyrrolidinyl]acetic acid		C₂₀H₂₈N₂O₄	详情	详情

Extended Information