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【结 构 式】

【分子编号】40016

【品名】tert-butyl 3-(2-methyl-2-propenyl)-2-oxo-1-pyrrolidinecarboxylate

【CA登记号】

【 分 子 式 】C13H21NO3

【 分 子 量 】239.31468

【元素组成】C 65.25% H 8.84% N 5.85% O 20.06%

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:(IV)

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.

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:(IV)

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.

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