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【结 构 式】

【药物名称】Ubenimex, Ubestatin, NK-421, Bestatin

【化学名称】(-)-N-[(2S,3R)-3-Amino-2-hydroxy-4-phenylbutyryl]-L-leucine

【CA登记号】58970-76-6

【 分 子 式 】C16H24N2O4

【 分 子 量 】308.38068

【开发单位】Nippon Kayaku (Originator)

【药理作用】IMMUNOMODULATING AGENTS, Immunostimulants, Leukemia Therapy, Lung Cancer Therapy, Oncolytic Drugs, Membrane Alanine Aminopeptidase (Aminopeptidase N) Inhibitors

合成路线1

The reaction of N-(2-oxo-2-phenylethyl)acetamide (I) with glyoxylic acid (II) by means of NaHCO3 in water gives threo-(2RS)-3-acetylamino-2-hydroxy-4-oxo-4-phenylbutanoic acid (III), which is reduced with H2 over Pd/C in acetic acid yielding threo-(2RS)-3-acetylamino-2-hydroxy-4-phenylbutanoic acid (IV). The treatment of (IV) with (S)-1-phenylethylamine followed by a fractionated crystallization affords (2S,3R)-3-acetyl-amino-2-hydroxy-4-phenylbutanoic acid (IV), which is hydrolyzed with HCl in refluxing water to afford (2R,3S)-3-amino-2-hydroxy-4-phenylbutanoic acid (V). The protection of (V) with benzyl S-4,6-dimethylpyrimidin-2-ylthiolcarbonate (VI) by means of triethylamine in dioxane - water gives (2S,3R)-3-benzyloxycarbonylamino-2-hydroxy-4-phenylbutanoic acid (VII), which is condensed whh benzyl (S)-leucinate (VIII) by means of di-cyclohexylcarbodiimide and p-toluenesulfonic acid yielding benzyl (2S,3R)-3-benzyloxycarbonylamino-2-hydroxy-4-phenylbutanoyl-(S)-leucinate (IX). Finally, this compound is deprotected by hydrogenation with H2 over Pd/C in acetic acid.

1 Umezawa, H.; Aoyagi, T.; Shirai, T.; Nishizawa, R.; Suzuki, M.; Saino, T. (Nippon Kayaku Co., Ltd.); Process for producing threo-3-amino-2-hydroxybutanoyl-aminoacetic acids, as well as novel intermediated therefor and process for producing them. DE 2947140; ES 486572; FR 2442227; GB 2090595; US 4281180 .
2 Castaner, J.; Blancafort, P.; Serradell, M.N.; Bestatin. Drugs Fut 1981, 6, 10, 604.
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) 14601 N-(2-oxo-2-phenylethyl)acetamide C10H11NO2 详情 详情
(II) 15618 2-Oxoacetic acid; Glyoxylic Acid 298-12-4 C2H2O3 详情 详情
(III) 32263 (2S,3S)-3-(acetamido)-2-hydroxy-4-oxo-4-phenylbutyric acid; threo-(2RS)-3-acetamido-2-hydroxy-4-oxo-4-phenylbutyric acid C12H13NO5 详情 详情
(IV) 32264 (2S,3R)-3-(acetamido)-2-hydroxy-4-phenylbutyric acid; threo-(2RS)-3-acetamido-2-hydroxy-4-phenylbutyric acid C12H15NO4 详情 详情
(V) 32265 (2S,3R)-3-amino-2-hydroxy-4-phenylbutyric acid; (2R,3S)-3-amino-2-hydroxy-4-phenylbutyric acid 62023-63-6 C10H13NO3 详情 详情
(VI) 32266 O-benzyl S-(4,6-dimethyl-2-pyrimidinyl) carbonothioate; benzyl S-4,6-dimethylpyrimidin-2-ylthiolcarbonate C14H14N2O2S 详情 详情
(VII) 32267 (2S,3R)-3-benzyIoxycarbonyIamino-2-hydroxy-4-phenylbutyric acid; (2S,3R)-3-[[(benzyloxy)carbonyl]amino]-2-hydroxy-4-phenylbutyric acid C18H19NO5 详情 详情
(VIII) 22252 Benzyl (2S)-2-amino-4-methylpentanoate; Benzyl (S)-leucinate C13H19NO2 详情 详情
(IX) 32268 benzyl (2S)-2-[((2S,3R)-3-[[(benzyloxy)carbonyl]amino]-2-hydroxy-4-phenylbutanoyl)amino]-4-methylpentanoate; benzyl (2S,3R)-3-Benzyloxycarbonylamino-2-hydroxy-4-phenylbutanoyI-(S)-Ieucinate C31H36N2O6 详情 详情
Extended Information