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【结 构 式】 
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【药物名称】Salbutamol sulfate, Albuterol sulfate, AH-3365, Pediavent, Ventoline, Ventolin, Proventil-HFA, Proventil, Volmax, Ventolin easy-breathe, Salbutamol Diskus, Proventil Repetabs, Ventolin Nebules, Buventol Easyhaler, Accuvent, Pulvinal salbutamol, Sultanol, 【化学名称】alpha1-[(tert-Butylamino)methyl]-4-hydroxy-m-xylene-alpha,alpha'-diol sulfate (2:1) 【CA登记号】51022-70-9, 18559-94-9 (free base) 【 分 子 式 】C26H44N2O10S 【 分 子 量 】576.71198 |
【开发单位】GlaxoSmithKline (Originator), 3M Pharmaceuticals (Not Determined), Ascent (Not Determined), Dey (Not Determined), Orion Corp. (Not Determined), Schering-Plough (Not Determined), Trinity Pharmaceuticals (Not Determined), Zambon (Not Determined), Ivax (Form 【药理作用】Asthma Therapy, Bronchodilators, Chronic Obstructive Pulmonary Diseases (COPD), Treatment of, RESPIRATORY DRUGS, beta2-Adrenoceptor Agonists |
合成路线1
The reaction of methyl 5-bromoacetylsalicylate (I) with benzyl tert-butylamine (II) in methyl ethyl ketone gives methyl 5-(N-benzyl-N-tert-butyl-gycyl)salicylate (III), which is reduced with LiAlH4 in refluxing THF yielding alpha'-(N-benzyl-N-tert-butylami-nomethyl)-4-hydroxy-m-xylene-alpha,alpha'-diol (IV). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in ethanol-water.
| 【1】 Castaner, J.; Blancafort, P.; Serradell, M.N.; Hopkins, S.J.; Albuterol. Drugs Fut 1979, 4, 9, 629. |
| 【2】 Lunts, L.H.C.; et al.; GB 1200886 . |
| 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) | 35836 | methyl 5-(2-bromoacetyl)-2-hydroxybenzoate | C10H9BrO4 | 详情 | 详情 | |
| (II) | 24700 | N-benzyl-2-methyl-2-propanamine | 3378-72-1 | C11H17N | 详情 | 详情 |
| (III) | 39613 | methyl 5-[2-[benzyl(tert-butyl)amino]acetyl]-2-hydroxybenzoate | C21H25NO4 | 详情 | 详情 | |
| (IV) | 39614 | 4-[2-[benzyl(tert-butyl)amino]-1-hydroxyethyl]-2-(hydroxymethyl)phenol | C20H27NO3 | 详情 | 详情 |
合成路线2
The chloromethylation of 4-hydroxyacetophenone (V) with formaldehyde and HCl in hot water gives 3-chloromethyl-4-hydroxyacetophenone (VI), which is treated with acetic anhydride-sodium acetate in refluxing acetic acid to afford 3-acetoxymethyl-4-acetoxyacetophenone (VII). The bromination of (VII) with Br2 in chloroform yields after hydrolysis 3-hydroxymethyl-4-hydroxyphenacyl bromide (VIII), which is condensed with benzyl tert-butylamine (II) in refluxing benzene giving alpha-(N-benzyl-N-tert-butylamino)-4-hydroxy-3-hydroxymethylacetophenone (IX). Finally, this compound is hydrogenated with H2 over Pd/C in ethanol. An alternative method of hydrogenation of (IX) is its reduction with NaBH4 - ethanol, to afford the previously obtained product (IV), which is reduced with H2 over Pd/C in ethanol.
| 【1】 Lunts, L.H.C.; et al.; GB 1200886 . |
| 【2】 Castaner, J.; Blancafort, P.; Serradell, M.N.; Hopkins, S.J.; Albuterol. Drugs Fut 1979, 4, 9, 629. |
| 【3】 Collin, D.T.; et al.; Saligenin analogs of sympathomimetic catecholamines. J Med Chem 1970, 13, 4, 674-680. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 24700 | N-benzyl-2-methyl-2-propanamine | 3378-72-1 | C11H17N | 详情 | 详情 |
| (IV) | 39614 | 4-[2-[benzyl(tert-butyl)amino]-1-hydroxyethyl]-2-(hydroxymethyl)phenol | C20H27NO3 | 详情 | 详情 | |
| (V) | 18123 | 1-(4-hydroxyphenyl)-1-ethanone; 4'-Hydroxyacetophenone | 99-93-4 | C8H8O2 | 详情 | 详情 |
| (VI) | 39615 | 1-[3-(chloromethyl)-4-hydroxyphenyl]-1-ethanone | C9H9ClO2 | 详情 | 详情 | |
| (VII) | 39616 | 5-acetyl-2-(acetoxy)benzyl acetate | C13H14O5 | 详情 | 详情 | |
| (VIII) | 39617 | 2-bromo-1-[4-hydroxy-3-(hydroxymethyl)phenyl]-1-ethanone | C9H9BrO3 | 详情 | 详情 | |
| (IX) | 39618 | 2-[benzyl(tert-butyl)amino]-1-[4-hydroxy-3-(hydroxymethyl)phenyl]-1-ethanone | C20H25NO3 | 详情 | 详情 |