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【结 构 式】 
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【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% |
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 |