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【结 构 式】 
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【分子编号】39615 【品名】1-[3-(chloromethyl)-4-hydroxyphenyl]-1-ethanone 【CA登记号】 |
【 分 子 式 】C9H9ClO2 【 分 子 量 】184.62196 【元素组成】C 58.55% H 4.91% Cl 19.2% O 17.33% |
合成路线1
该中间体在本合成路线中的序号：(VI)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 |
合成路线2
该中间体在本合成路线中的序号：(XIII)An alternative method, suitable for large-scale synthesis, has been described: The chloromethylation of 4'-hydroxyacetophenone (XII) using formaldehyde and HCl gave (XIII). Displacement of the chloride group with NaCN provided nitrile (XIV), which was further hydrolyzed to the carboxylic acid (XV). Esterification of (XV) with methanol and sulfuric acid yields (XVI), whose phenolic hydroxyl group was protected as the benzyl ether (XVII) by alkylation with benzyl chloride. Subsequent bromination of ketone (XVII) yielded the phenacyl bromide (XVIII). The chiral amino alcohol (XX) was prepared from (-)-camphor (XIX) by ketone oxidation in position alpha with SeO2, followed by condensation with hydroxylamine and reduction with LiAlH4. Asymmetric reduction of the bromo ketone (XVIII) with borane in the presence of aluminum triethoxide and the chiral auxiliary (XX) provided the desired (R)-bromohydrin (XXI). The hydroxyl groups of (XXI) were then protected by silylation with tert-butyldimethylsilyl chloride, yielding (XXII). Condensation of the silyl-protected bromide (XXII) with (S)-2[(2-amino-1,2,3,4-tetrahydronaphthalen-7-yl)oxy]-N,N-dimethylacetamide (XXIII) furnished adduct (XXIV).
| 【1】 Yanagi, T.; et al.; The practical synthesis of a uterine relaxant, bis (2-{[2S)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(2-hydroxyethyl)-phenyl]ethyl}amino)-1,2,3,4-tetrahydronaphthalen-7-yl]oxy}-N,N-dimethylacetamide)sulfate (KUR-1246). Chem Pharm Bull 2001, 49, 8, 1018. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 18123 | 1-(4-hydroxyphenyl)-1-ethanone; 4'-Hydroxyacetophenone | 99-93-4 | C8H8O2 | 详情 | 详情 |
| (XIII) | 39615 | 1-[3-(chloromethyl)-4-hydroxyphenyl]-1-ethanone | C9H9ClO2 | 详情 | 详情 | |
| (XIV) | 50683 | 2-(5-acetyl-2-hydroxyphenyl)acetonitrile | C10H9NO2 | 详情 | 详情 | |
| (XV) | 50684 | 2-(5-acetyl-2-hydroxyphenyl)acetic acid | C10H10O4 | 详情 | 详情 | |
| (XVI) | 50685 | methyl 2-(5-acetyl-2-hydroxyphenyl)acetate | C11H12O4 | 详情 | 详情 | |
| (XVII) | 50686 | methyl 2-[5-acetyl-2-(benzyloxy)phenyl]acetate | C18H18O4 | 详情 | 详情 | |
| (XVIII) | 50687 | methyl 2-[2-(benzyloxy)-5-(2-bromoacetyl)phenyl]acetate | C18H17BrO4 | 详情 | 详情 | |
| (XIX) | 17415 | (1R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one | 464-49-3 | C10H16O | 详情 | 详情 |
| (XX) | 50688 | (1R,2S,3R,4S)-3-amino-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol | C10H19NO | 详情 | 详情 | |
| (XXI) | 50689 | (1R)-1-[4-(benzyloxy)-3-(2-hydroxyethyl)phenyl]-2-bromo-1-ethanol | C17H19BrO3 | 详情 | 详情 | |
| (XXII) | 50690 | ([(1R)-1-[4-(benzyloxy)-3-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)phenyl]-2-bromoethyl]oxy)(tert-butyl)dimethylsilane; benzyl 4-((1R)-2-bromo-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)phenyl ether | C29H47BrO3Si2 | 详情 | 详情 | |
| (XXIII) | 50691 | 2-[[(7S)-7-amino-5,6,7,8-tetrahydro-2-naphthalenyl]oxy]-N,N-dimethylacetamide | C14H20N2O2 | 详情 | 详情 | |
| (XXIV) | 50692 | 2-([(7S)-7-[((2R)-2-[4-(benzyloxy)-3-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)phenyl]-2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)amino]-5,6,7,8-tetrahydro-2-naphthalenyl]oxy)-N,N-dimethylacetamide | C43H66N2O5Si2 | 详情 | 详情 |