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【结 构 式】 
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【药物名称】 【化学名称】N1-[2-Oxo-1(S)-(2-phenylethyl)-3-(3-phenylpropylsulfanyl)propyl]-N2-(pyridin-3-ylmethyloxycarbonyl)-L-leucinamide 【CA登记号】 【 分 子 式 】C33H41N3O4S 【 分 子 量 】575.77642 |
【开发单位】University of California, Berkeley (Originator) 【药理作用】ANTIINFECTIVE THERAPY, Antitrypanosomals, Treatment of Protozoal Diseases, Cysteine Protease Inhibitors |
合成路线1
The intermediate N-(pyridin-3-ylmethoxycarbonyl)-L-leucine (V) has been obtained as follows: L-Leucine methyl ester (I) was converted into the isocyanate (II) by conventional methods, and the resulting compound was condensed with 3-pyridylmethanol (III) to yield the N-acylated leucine methyl ester (IV). Finally, this compound was hydrolyzed with LiOH to afford the desired intermediate N-(pyridin-3-ylmethoxycarbonyl)-L-leucine (V).
| 【1】 Ellman, J.A.; Lee, A.; Huang, L. ; Identification of potent and selective mechanism-based inhibitors of the cysteine protease cruzain using solid-phase parallel synthesis. J Med Chem 2002, 45, 3, 676. |
| 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) | 27709 | methyl (2S)-2-amino-4-methylpentanoate | C7H15NO2 | 详情 | 详情 | |
| (II) | 54421 | methyl (2S)-2-isocyanato-4-methylpentanoate | C8H13NO3 | 详情 | 详情 | |
| (III) | 15798 | 3-Pyridinemethanol; 3-pyridinylmethanol | 100-55-0 | C6H7NO | 详情 | 详情 |
| (IV) | 54422 | methyl (2S)-4-methyl-2-{[(3-pyridinylmethoxy)carbonyl]amino}pentanoate | C14H20N2O4 | 详情 | 详情 | |
| (V) | 54423 | (2S)-4-methyl-2-{[(3-pyridinylmethoxy)carbonyl]amino}pentanoic acid | C13H18N2O4 | 详情 | 详情 |
合成路线2
3(S)-(Allyloxycarbonylamino)-1-chloro-5-phenyl-2-pentanone (VI) is linked to a carbazate resin (VII) to yield the resin-supported compound (VIII) suitable for solid-phase synthesis. The condensation of (VIII) with 3-phenylpropylmercaptan (IX) by means of DIEA in DMF affords the adduct (X), which is deprotected at the allyloxycarbonylamino group by means of Pd(PPh3)4 to provide the amino resin (XI). The condensation of (XI) with the previously described intermediate (V) by means of PyBOP, HOAt and DIEA in DMF gives dipeptide resin (XII). Finally, the cleavage of the target compound from the resin (XII) is performed by means of TFA in trifluoroethanol/water.
| 【1】 Ellman, J.A.; Lee, A.; Huang, L. ; Identification of potent and selective mechanism-based inhibitors of the cysteine protease cruzain using solid-phase parallel synthesis. J Med Chem 2002, 45, 3, 676. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 54423 | (2S)-4-methyl-2-{[(3-pyridinylmethoxy)carbonyl]amino}pentanoic acid | C13H18N2O4 | 详情 | 详情 | |
| (VI) | 54424 | allyl (1S)-3-chloro-2-oxo-1-phenethylpropylcarbamate | C15H18ClNO3 | 详情 | 详情 | |
| (VII) | 12256 | 2,4,5-Trifluoro-3-methoxybenzonitrile | C8H4F3NO | 详情 | 详情 | |
| (VIII) | 54425 | methyl 2-[(E,2S)-2-{[(allyloxy)carbonyl]amino}-1-(chloromethyl)-4-phenylbutylidene]-1-hydrazinecarboxylate | C17H22ClN3O4 | 详情 | 详情 | |
| (IX) | 54426 | 3-Phenylpropyl mercaptan; 3-Phenyl-1-propanethiol | 24734-68-7 | C9H12S | 详情 | 详情 |
| (X) | 54427 | methyl 2-((E,2S)-2-{[(allyloxy)carbonyl]amino}-4-phenyl-1-{[(3-phenylpropyl)sulfanyl]methyl}butylidene)-1-hydrazinecarboxylate | C26H33N3O4S | 详情 | 详情 | |
| (XI) | 54428 | methyl 2-((E,2S)-2-amino-4-phenyl-1-{[(3-phenylpropyl)sulfanyl]methyl}butylidene)-1-hydrazinecarboxylate | C22H29N3O2S | 详情 | 详情 | |
| (XII) | 54429 | methyl (E,5S,8S)-8-isobutyl-7,10-dioxo-5-phenethyl-4-{[(3-phenylpropyl)sulfanyl]methyl}-12-(3-pyridinyl)-11-oxa-2,3,6,9-tetraaza-3-dodecen-1-oate | C35H45N5O5S | 详情 | 详情 |