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【结 构 式】 
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【药物名称】L-685458 【化学名称】N-[2(R)-Benzyl-5(S)-(tert-butoxycarboxamido)-4(R)-hydroxy-6-phenylhexanoyl]-L-leucyl-L-phenylalanylamide 【CA登记号】292632-98-5 【 分 子 式 】C39H52N4O6 【 分 子 量 】672.87249 |
【开发单位】Merck Sharp & Dohme (Originator) 【药理作用】Alzheimer's Dementia, Treatment of , Cognition Disorders, Treatment of, NEUROLOGIC DRUGS, gamma-Secretase Inhibitors |
合成路线1
The alkylation of N-[1(S)-(5-oxotetrahydrofuran-2(R)-yl)-2-phenylethyl]carbamic acid tert-butyl ester (I) with benzaldehyde (II) by means of LDA in THF, followed by a treatment with Ac2O and TEA at 120 C, gives the benzylidene derivative (III), which is hydrogenated with H2 over Pd/C in methanol/ethyl acetate to yield N-[1(S)-[4(R)-benzyl-5-oxotetrahydrofuran-2(R)-yl]-2-phenylethyl]carbamic acid tert-butyl ester (IV). The hydrolysis of (IV) with NaOH in dimethoxyethane/water affords the hexanoic acid (V), which is finally condensed with the dipeptide L-leucyl-L-phenylalaninamide (VI) by means of EDC and HOBT in DMF to provide the target acylated dipeptide.
| 【1】 Hunt, P.A.; Harrison, T.; Castro Pineiro, J.L.; Nadin, A.J. (Merck Sharp & Dohme Ltd.); gamma-Secretase inhibitors. WO 0153255 . |
| 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) | 52631 | 1,1-dimethylethyl 1-(5-oxotetrahydro-2-furanyl)-2-phenylethylcarbamate | C17H23NO4 | 详情 | 详情 | |
| (II) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (III) | 52632 | 1,1-dimethylethyl 1-[5-oxo-4-(phenylmethylidene)tetrahydro-2-furanyl]-2-phenylethylcarbamate | C24H27NO4 | 详情 | 详情 | |
| (IV) | 52633 | 1,1-dimethylethyl 1-[5-oxo-4-(phenylmethyl)tetrahydro-2-furanyl]-2-phenylethylcarbamate | C24H29NO4 | 详情 | 详情 | |
| (V) | 52634 | 5-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-4-hydroxy-6-phenyl-2-(phenylmethyl)hexanoic acid | C24H31NO5 | 详情 | 详情 | |
| (VI) | 52635 | 2-amino-N-[2-amino-2-oxo-1-(phenylmethyl)ethyl]-4-methylpentanamide | C15H23N3O2 | 详情 | 详情 |