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【结 构 式】 
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【药物名称】TAK-726 【化学名称】1-Naphthylsulfonyl-L-isoleucyl-L-tryptophanal 【CA登记号】161709-56-4 【 分 子 式 】C27H29N3O4S 【 分 子 量 】491.61388 |
【开发单位】Takeda (Originator) 【药理作用】Bone Diseases, Treatment of, Bone Resorption Inhibitors, METABOLIC DRUGS, Treatment of Osteoporosis |
合成路线1
Title compound was prepared by two related ways: N-(Benzyloxycarbonyl)-L-tryptofanol (I) was deprotected by hydrogenolysis in the presence of Pd/C. The resulting tryptofanol (II) was then coupled with N-(benzyloxycarbonyl)-L-isoleucine (III), using 1-(3-diethylaminopropyl)-3-ethylcarbodiimide.HCl (EDC) and 1-hydroxybenzotriazole (HOBt) to provide (IV). Subsequent hydrogenolytic deprotection gave amine (V), which was condensed with 1-naphthalenylsulfonyl chloride (VI) in the presence of 4-(dimethylamino)pyridine to afford sulfonamide (VII). Finally, oxidation with DMSO in the presence of SO3-pyridine complex yielded the aldehyde.
| 【1】 Yasuma, T.; Oi, S.; Choh, N.; Nomura, T.; Furuyama, N.; Nishimura, A.; Fujisawa, Y.; Sohda, T.; Synthesis of peptide aldehyde derivatives as selective inhibitors of human cathepsin L and their inhibitory effect on bone resorption. J Med Chem 1998, 41, 22, 4301. |
| 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) | 18645 | benzyl (1S)-2-hydroxy-1-(1H-indol-3-ylmethyl)ethylcarbamate | C19H20N2O3 | 详情 | 详情 | |
| (II) | 18646 | (2S)-2-amino-3-(1H-indol-3-yl)-1-propanol | C11H14N2O | 详情 | 详情 | |
| (III) | 23508 | (2S,3S)-2-[[(benzyloxy)carbonyl]amino]-3-methylpentanoic acid | 3160-59-6 | C14H19NO4 | 详情 | 详情 |
| (IV) | 18648 | benzyl (1S,2S)-1-([[(1S)-2-hydroxy-1-(1H-indol-3-ylmethyl)ethyl]amino]carbonyl)-2-methylbutylcarbamate | C25H31N3O4 | 详情 | 详情 | |
| (V) | 18649 | (2S,3S)-2-amino-N-[(1S)-2-hydroxy-1-(1H-indol-3-ylmethyl)ethyl]-3-methylpentanamide | C17H25N3O2 | 详情 | 详情 | |
| (VI) | 18650 | 1-naphthalenesulfonyl chloride | 85-46-1 | C10H7ClO2S | 详情 | 详情 |
| (VII) | 18651 | (2S,3S)-N-[(1S)-2-hydroxy-1-(1H-indol-3-ylmethyl)ethyl]-3-methyl-2-[(1-naphthylsulfonyl)amino]pentanamide | C27H31N3O4S | 详情 | 详情 |
合成路线2
Alternatively, N-(benzyloxycarbonyl)-L-Trp (VIII) was condensed with N,O-dimethylhydroxylamine in the presence of EDC and HOBt to give N-(methoxy)amide (IX). Hydrogenolytic deprotection produced amine (X), which was coupled with Z-Ile (III) to afford dipeptide (XI). Subsequent deprotection, and coupling of the resulting amine (XII) with sulfonyl chloride (VI) gave sulfonamide (XIII). Then, reduction of the N-(methoxy)amide with diisobutylaluminum hydride furnished the target aldehyde
| 【1】 Yasuma, T.; Oi, S.; Choh, N.; Nomura, T.; Furuyama, N.; Nishimura, A.; Fujisawa, Y.; Sohda, T.; Synthesis of peptide aldehyde derivatives as selective inhibitors of human cathepsin L and their inhibitory effect on bone resorption. J Med Chem 1998, 41, 22, 4301. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 23508 | (2S,3S)-2-[[(benzyloxy)carbonyl]amino]-3-methylpentanoic acid | 3160-59-6 | C14H19NO4 | 详情 | 详情 |
| (VI) | 18650 | 1-naphthalenesulfonyl chloride | 85-46-1 | C10H7ClO2S | 详情 | 详情 |
| (VIII) | 18652 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-(1H-indol-3-yl)propionic acid | 7432-21-5 | C19H18N2O4 | 详情 | 详情 |
| (IX) | 18653 | benzyl (1S)-1-(1H-indol-3-ylmethyl)-2-[methoxy(methyl)amino]-2-oxoethylcarbamate | C21H23N3O4 | 详情 | 详情 | |
| (X) | 18654 | (2S)-2-amino-3-(1H-indol-3-yl)-N-methoxy-N-methylpropanamide | C13H17N3O2 | 详情 | 详情 | |
| (XI) | 18655 | benzyl (1S,2S)-1-[([(1S)-1-(1H-indol-3-ylmethyl)-2-[methoxy(methyl)amino]-2-oxoethyl]amino)carbonyl]-2-methylbutylcarbamate | C27H34N4O5 | 详情 | 详情 | |
| (XII) | 18656 | (2S,3S)-2-amino-N-[(1S)-1-(1H-indol-3-ylmethyl)-2-[methoxy(methyl)amino]-2-oxoethyl]-3-methylpentanamide | C19H28N4O3 | 详情 | 详情 | |
| (XIII) | 18657 | (2S,3S)-N-[(1S)-1-(1H-indol-3-ylmethyl)-2-[methoxy(methyl)amino]-2-oxoethyl]-3-methyl-2-[(1-naphthylsulfonyl)amino]pentanamide | C29H34N4O5S | 详情 | 详情 |