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【结 构 式】 
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【分子编号】40627 【品名】tert-butyl (1S)-3-methyl-1-[(2R)-5-oxotetrahydro-2-furanyl]butylcarbamate 【CA登记号】 |
【 分 子 式 】C14H25NO4 【 分 子 量 】271.35684 【元素组成】C 61.97% H 9.29% N 5.16% O 23.58% |
合成路线1
该中间体在本合成路线中的序号：(VIa)Boc-Leucine (I) was converted to Weinreb amide (II) by activation with isobutyl chloroformate and N-methylpiperidine, followed by treatment of the resulting mixed anhydride with N,O-dimethylhydroxylamine. Reduction of (II) with LiAlH4 provided the aldehyde (III), which was condensed with the lithium anion of ethyl propiolate (IV) to furnish the acetylenic alcohol (Va-b) as an inseparable mixture of diastereomers. Catalytic hydrogenation of the triple bond of (Va-b) over Pd/BaSO4, followed by acid-catalyzed lactonization of the resulting hydroxy ester provided the diastereomeric mixture of gamma-lactones (VIa-b). After separation by column chromatography, alkylation of the desired isomer employing iodomethane and lithium hexamethyldisilazide at -78 C provided the desired alpha-methyl lactone (VII), along with a small amount of the corresponding epimer. Lactone (VII) hydrolysis using LiOH gave hydroxy acid (VIII), which was further protected as the silyl ether (IX) with tert-butyldimethylsilyl chloride and imidazole. The Boc protecting group of (IX) was selectively removed by treatment with trifluoroacetic acid in CH2Cl2 at 0 C, and the resulting amine (X) was treated with Fmoc-succinimide to provide the Fmoc-protected intermediate (XI).
| 【1】 Lin, X.; Shin, D.; Downs, D.; Tang, J.; Koelsch, G.; Ghosh, A.K.; Ermolieff, J.; Design of potent inhibitors for human brain memapsin 2 (beta-secretase). J Am Chem Soc 2000, 122, 14, 3522. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (Va) | 40625 | ethyl (4R,5S)-5-[(tert-butoxycarbonyl)amino]-4-hydroxy-7-methyl-2-octynoate | C16H27NO5 | 详情 | 详情 | |
| (Vb) | 40626 | ethyl (4S,5S)-5-[(tert-butoxycarbonyl)amino]-4-hydroxy-7-methyl-2-octynoate | C16H27NO5 | 详情 | 详情 | |
| (VIa) | 40627 | tert-butyl (1S)-3-methyl-1-[(2R)-5-oxotetrahydro-2-furanyl]butylcarbamate | C14H25NO4 | 详情 | 详情 | |
| (VIb) | 40628 | tert-butyl (1S)-3-methyl-1-[(2S)-5-oxotetrahydro-2-furanyl]butylcarbamate | C14H25NO4 | 详情 | 详情 | |
| (I) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
| (II) | 40395 | tert-butyl (1S)-1-[[methoxy(methyl)amino]carbonyl]-3-methylbutylcarbamate | C13H26N2O4 | 详情 | 详情 | |
| (III) | 27058 | tert-butyl (1S)-1-formyl-3-methylbutylcarbamate | C11H21NO3 | 详情 | 详情 | |
| (IV) | 35333 | ethyl propiolate | 623-47-2 | C5H6O2 | 详情 | 详情 |
| (VII) | 40629 | tert-butyl (1S)-3-methyl-1-[(2S,4R)-4-methyl-5-oxotetrahydro-2-furanyl]butylcarbamate | C15H27NO4 | 详情 | 详情 | |
| (VIII) | 40630 | (2R,4S,5S)-5-[(tert-butoxycarbonyl)amino]-4-hydroxy-2,7-dimethyloctanoic acid | C15H29NO5 | 详情 | 详情 | |
| (IX) | 40631 | (2R,4S,5S)-5-[(tert-butoxycarbonyl)amino]-4-[[tert-butyl(dimethyl)silyl]oxy]-2,7-dimethyloctanoic acid | C21H43NO5Si | 详情 | 详情 | |
| (X) | 40632 | (2R,4S,5S)-5-amino-4-[[tert-butyl(dimethyl)silyl]oxy]-2,7-dimethyloctanoic acid | C16H35NO3Si | 详情 | 详情 | |
| (XI) | 40633 | (2R,4S,5S)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-2,7-dimethyloctanoic acid | C31H45NO5Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIa)Boc-Leucine (I) was converted to Weinreb amide (II) by activation with isobutyl chloroformate and N-methylpiperidine, followed by treatment of the resulting mixed anhydride with N,O-dimethylhydroxylamine. Reduction of (II) with LiAlH4 provided the aldehyde (III), which was condensed with the lithium anion of ethyl propiolate (IV) to furnish the acetylenic alcohol (Va-b) as an inseparable mixture of diastereomers. Catalytic hydrogenation of the triple bond of (Va-b) over Pd/BaSO4, followed by acid-catalyzed lactonization of the resulting hydroxy ester provided the diastereomeric mixture of gamma-lactones (VIa-b). After separation by column chromatography, alkylation of the desired isomer employing iodomethane and lithium hexamethyldisilazide at -78 C provided the desired alpha-methyl lactone (VII), along with a small amount of the corresponding epimer. Lactone (VII) hydrolysis using LiOH gave hydroxy acid (VIII), which was further protected as the silyl ether (IX) with tert-butyldimethylsilyl chloride and imidazole. The Boc protecting group of (IX) was selectively removed by treatment with trifluoroacetic acid in CH2Cl2 at 0 C, and the resulting amine (X) was treated with Fmoc-succinimide to provide the Fmoc-protected intermediate (XI).
| 【1】 Lin, X.; Shin, D.; Downs, D.; Tang, J.; Koelsch, G.; Ghosh, A.K.; Ermolieff, J.; Design of potent inhibitors for human brain memapsin 2 (beta-secretase). J Am Chem Soc 2000, 122, 14, 3522. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (Va) | 40625 | ethyl (4R,5S)-5-[(tert-butoxycarbonyl)amino]-4-hydroxy-7-methyl-2-octynoate | C16H27NO5 | 详情 | 详情 | |
| (Vb) | 40626 | ethyl (4S,5S)-5-[(tert-butoxycarbonyl)amino]-4-hydroxy-7-methyl-2-octynoate | C16H27NO5 | 详情 | 详情 | |
| (VIa) | 40627 | tert-butyl (1S)-3-methyl-1-[(2R)-5-oxotetrahydro-2-furanyl]butylcarbamate | C14H25NO4 | 详情 | 详情 | |
| (VIb) | 40628 | tert-butyl (1S)-3-methyl-1-[(2S)-5-oxotetrahydro-2-furanyl]butylcarbamate | C14H25NO4 | 详情 | 详情 | |
| (I) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
| (II) | 40395 | tert-butyl (1S)-1-[[methoxy(methyl)amino]carbonyl]-3-methylbutylcarbamate | C13H26N2O4 | 详情 | 详情 | |
| (III) | 27058 | tert-butyl (1S)-1-formyl-3-methylbutylcarbamate | C11H21NO3 | 详情 | 详情 | |
| (IV) | 35333 | ethyl propiolate | 623-47-2 | C5H6O2 | 详情 | 详情 |
| (VII) | 40629 | tert-butyl (1S)-3-methyl-1-[(2S,4R)-4-methyl-5-oxotetrahydro-2-furanyl]butylcarbamate | C15H27NO4 | 详情 | 详情 | |
| (VIII) | 40630 | (2R,4S,5S)-5-[(tert-butoxycarbonyl)amino]-4-hydroxy-2,7-dimethyloctanoic acid | C15H29NO5 | 详情 | 详情 | |
| (IX) | 40631 | (2R,4S,5S)-5-[(tert-butoxycarbonyl)amino]-4-[[tert-butyl(dimethyl)silyl]oxy]-2,7-dimethyloctanoic acid | C21H43NO5Si | 详情 | 详情 | |
| (X) | 40632 | (2R,4S,5S)-5-amino-4-[[tert-butyl(dimethyl)silyl]oxy]-2,7-dimethyloctanoic acid | C16H35NO3Si | 详情 | 详情 | |
| (XI) | 40633 | (2R,4S,5S)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-2,7-dimethyloctanoic acid | C31H45NO5Si | 详情 | 详情 |