药物详细合成路线
| Name | Ubenimex;Ubestatin;NK-421;Bestatin | | Chemical Name | (-)-N-[(2S,3R)-3-Amino-2-hydroxy-4-phenylbutyryl]-L-leucine | | CAS | 58970-76-6 | | Related CAS | | | Formula | C16H24N2O4 | | Structure |  | | Formula Weight | 308.38068 | | Stage | 上市-1987 | | Company | Nippon Kayaku (Originator) | | Activity/Mechanism | IMMUNOMODULATING AGENTS, Immunostimulants, Leukemia Therapy, Lung Cancer Therapy, Oncolytic Drugs, Membrane Alanine Aminopeptidase (Aminopeptidase N) Inhibitors | | Syn. Route | 1 | | Route 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. | | |  | | List of intermediates | No. | | 3-phenylcyclobutanecarboxylic acid | (i) | | tert-butyl(diphenyl)silyl (z)-7-((1r,2r,3r)-2-[(e,3s)-3-[(2-bromoacetyl)oxy]-1-octenyl]-3-hydroxy-5-oxocyclopentyl)-5-heptenoate | (ii) | | n-[(e)-amino[(2-methoxyethyl)amino]methylidene]thiourea | (viii) | | 3-(4,5,6,7-tetrahydro-1h-indol-3-yl)propionic acid | (iii) | | 3-(2-formyl-4,5,6,7-tetrahydro-1h-indol-3-yl)propionic acid | (iv) | | 7-amino-4-methyl-1h-indole-3-carbonitrile | (v) | | 5-bromo-1,3-dihydro-2h-indol-2-one | (vi) | | 5-methyl-2-nitrobenzoyl chloride | (vii) | | 5-methyl-2-nitrophenylamine; 5-methyl-2-nitroaniline | (ix) | | | Reference 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 . Reference 2: castaner, j.; blancafort, p.; serradell, m.n.; bestatin. drugs fut 1981, 6, 10, 604. |
|
来源:药化网
作者:药化小编
摘要:本文合成路线介绍的是药物中文名乌苯美司；英文名Ubenimex;Ubestatin;NK-421;Bestatin；CAS[58970-76-6]
|
