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【结 构 式】 
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【药物名称】JE-1520 【化学名称】3-[3(S)-(2-Ethyl-3-hydroxybenzamido)-2(S)-hydroxy-4-phenylbutyryl]-5,5-dimethyl-N-(2-methylbenzyl)thiazolidine-4(R)-carboxamide 【CA登记号】186538-01-2 【 分 子 式 】C33H39N3O5S 【 分 子 量 】589.75988 |
【开发单位】Japan Energy (Originator) 【药理作用】AIDS Medicines, Anti-HIV Agents, ANTIINFECTIVE THERAPY, HIV Protease Inhibitors |
合成路线1
Treatment of penicillamine (I) with formaldehyde produced thiazolidine (II), which was then protected with Boc2O to give carbamate (III). Coupling of (III) with 2-methylbenzylamine (IV) by means of either diphenylphosphoryl chloride (DPP-Cl) or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide-HCl (EDC) afforded the corresponding amide (V). After acid cleavage of the Boc group of (V), the deprotected thiazolidine (VI) was coupled with N-Boc-(S,S)-3-amino-2-hydroxy-4-phenylbutyric acid (VII) using EDC to give diamide (VIII). Further acid deprotection of the Boc group of (VIII) yielded (IX). This was finally coupled with 2-ethyl-3-hydroxybenzoic acid (X) to furnish the title compound. Alternatively, amine (IX) was coupled with 3-acetoxy-2-ethylbenzoic acid (XI) to afford (XII), which was then deacetylated using NaOH in MeOH.
| 【1】 Kiso, Y.; Design and synthesis of a covalently linked HIV-1 protease dimer analog and peptidomimetic inhibitors. Yuki Gosei Kagaku Kyokaishi 1998, 56, 11, 896. |
| 【2】 Mimoto, T.; Takaku, H.; Kato, R.; et al.; Structure-activity relationship of small-sized HIV protease inhibitors containing allophenylnorstatine. J Med Chem 1999, 42, 10, 1789. |
| 【3】 Kato, R.; Mimoto, T.; Fukazawa, T.; Morohashi, N.; Kiso, Y. (Japan Energy Corp.); HIV-protease inhibitors. CA 2179935; EP 0751145; JP 1998025242 . |
| 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) | 12567 | (2S)-2-Amino-3-methyl-3-sulfanylbutyric acid; Penicillamine; 3-Mercapto-L-valine | 1113-41-3 | C5H11NO2S | 详情 | 详情 |
| (II) | 34776 | (4R)-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid | 72778-00-8 | C6H11NO2S | 详情 | 详情 |
| (III) | 34777 | (4R)-3-(tert-butoxycarbonyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid | C11H19NO4S | 详情 | 详情 | |
| (IV) | 34778 | (2-methylphenyl)methanamine; 2-methylbenzylamine | 89-93-0 | C8H11N | 详情 | 详情 |
| (V) | 34779 | tert-butyl (4R)-5,5-dimethyl-4-[[(2-methylbenzyl)amino]carbonyl]-1,3-thiazolidine-3-carboxylate | C19H28N2O3S | 详情 | 详情 | |
| (VI) | 34780 | (4R)-5,5-dimethyl-N-(2-methylbenzyl)-1,3-thiazolidine-4-carboxamide | C14H20N2OS | 详情 | 详情 | |
| (VII) | 34781 | (2S,3S)-3-[(tert-butoxycarbonyl)amino]-2-methyl-4-phenylbutyric acid | C16H23NO4 | 详情 | 详情 | |
| (VIII) | 34782 | tert-butyl (1S,2S)-1-benzyl-3-((4R)-5,5-dimethyl-4-[[(2-methylbenzyl)amino]carbonyl]-1,3-thiazolidin-3-yl)-2-methyl-3-oxopropylcarbamate | C30H41N3O4S | 详情 | 详情 | |
| (IX) | 34783 | (4R)-3-[(2S,3S)-3-amino-2-methyl-4-phenylbutanoyl]-5,5-dimethyl-N-(2-methylbenzyl)-1,3-thiazolidine-4-carboxamide | C25H33N3O2S | 详情 | 详情 | |
| (X) | 34786 | 2-ethyl-3-hydroxybenzoic acid | C9H10O3 | 详情 | 详情 | |
| (XI) | 34787 | 3-(acetoxy)-2-ethylbenzoic acid | C11H12O4 | 详情 | 详情 | |
| (XII) | 34788 | 3-([[(1S,2S)-1-benzyl-3-((4R)-5,5-dimethyl-4-[[(2-methylbenzyl)amino]carbonyl]-1,3-thiazolidin-3-yl)-2-methyl-3-oxopropyl]amino]carbonyl)-2-ethylphenyl acetate | C36H43N3O5S | 详情 | 详情 |