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【结 构 式】

【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
Extended Information