|
【结 构 式】 
|
【药物名称】 【化学名称】N-[1(S)-Methylhexyl]carbamic acid 3-(1H-imidazol-4-yl)propyl ester fumarate 【CA登记号】221155-45-9 (free base), 184022-46-6 (undefined isomer, free base) 【 分 子 式 】C18H29N3O6 【 分 子 量 】383.44833 |
【开发单位】Bioprojet (Originator), INSERM (Originator) 【药理作用】Cognition Disorders, Treatment of, NEUROLOGIC DRUGS, Histamine H3 Receptor Antagonists |
合成路线1
Hydrogenation of urocanic acid (I) provided 3-(imidazol-4-yl)propionic acid (II), which was esterified with EtOH and H2SO4 to give ethyl ester (III). Tritylation of (III) with triphenylmethyl chloride afforded (IV), and subsequent reduction using LiAlH4 yielded alcohol (V). Acid cleavage of the trityl protecting group of (V) furnished imidazolylpropanol (VI). Isocyanate (VIII) was prepared from (S)-2-heptylamine (VII) by treatment with diphosgene and a catalytic amount of activated charcoal. Then, condensation between isocyanate (VIII) and alcohol (V) in refluxing acetonitrile generated the corresponding carbamate. The title compound was isolated after conversion to the corresponding hydrogen maleate salt Hydrogenation of urocanic acid (I) provided 3-(imidazol-4-yl)propionic acid (II), which was esterified with EtOH and H2SO4 to give ethyl ester (III). Tritylation of (III) with triphenylmethyl chloride afforded (IV), and subsequent reduction using LiAlH4 yielded alcohol (V). Acid cleavage of the trityl protecting group of (V) furnished imidazolylpropanol (VI). Isocyanate (VIII) was prepared from (S)-2-heptylamine (VII) by treatment with diphosgene and a catalytic amount of activated charcoal. Then, condensation between isocyanate (VIII) and alcohol (V) in refluxing acetonitrile generated the corresponding carbamate. The title compound was isolated after conversion to the corresponding hydrogen maleate salt.
| 【1】 Kiec-Kononowicz, K.; Sasse, A.; Stark, H.; et al.; Development of chiral N-alkylcarbamates as new leads for potent and selective H3-receptor antagonists: Synthesis, capillary electrophoresis, and in vitro and oral in vivo activity. J Med Chem 1999, 42, 4, 593. |
| 【2】 Imidazole derivs. as histamine receptor H3 (ant)agonists. EP 0760811; FR 2732017; JP 1998501001; WO 9629315 . |
| 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) | 27420 | Urocanic acid; (E)-3-(1H-imidazol-4-yl)-2-propenoic acid | 104-98-3 | C6H6N2O2 | 详情 | 详情 |
| (II) | 27421 | 3-(1H-imidazol-4-yl)propionic acid | C6H8N2O2 | 详情 | 详情 | |
| (III) | 27422 | ethyl 3-(1H-imidazol-4-yl)propanoate | C8H12N2O2 | 详情 | 详情 | |
| (IV) | 27423 | ethyl 3-(1-trityl-1H-imidazol-4-yl)propanoate | C27H26N2O2 | 详情 | 详情 | |
| (V) | 27424 | 3-(1-trityl-1H-imidazol-4-yl)-1-propanol | C25H24N2O | 详情 | 详情 | |
| (VI) | 21245 | 3-(1H-imidazol-4-yl)-1-propanol | C6H10N2O | 详情 | 详情 | |
| (VII) | 35809 | (1S)-1-methylhexylamine; (2S)-2-heptanamine | 44745-29-1 | C7H17N | 详情 | 详情 |
| (VIII) | 35810 | (2S)-2-isocyanatoheptane; (1S)-1-methylhexyl isocyanate | C8H15NO | 详情 | 详情 |