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【结 构 式】 
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【分子编号】35837 【品名】N-benzyl-6-(4-phenylbutoxy)-1-hexanamine; N-benzyl-N-[6-(4-phenylbutoxy)hexyl]amine 【CA登记号】 |
【 分 子 式 】C23H33NO 【 分 子 量 】339.52116 【元素组成】C 81.37% H 9.8% N 4.13% O 4.71% |
合成路线1
该中间体在本合成路线中的序号：(V)The Friedel-Crafts condensation of 2-hydroxybenzoic acid methyl ester (I) with 13C-labeled acetyl chloride (II) by means of AlCl3 in dichloromethane gives 5-acetyl-2-hydroxybenzoic acid methyl ester (III), which is brominated with Br2 in CHCl3 yielding the bromoacetyl compound (IV). The condensation of (IV) with the secondary amine (V) by means of DIEA in THF affords the tertiary amine (VI), which is reduced with LiAlD4 in refluxing ethyl ether to provide the trideuterated triol (VII). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in ethanol.
| 【1】 Goodwin, T.E.; et al.; Synthesis of 13C,2H3-salmeterol: An analytical internal standard for pharmacokinetic studies. J Label Compd Radiopharm 2000, 43, 1, 65. |
| 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) | 15754 | methyl salicylate | 119-36-8 | C8H8O3 | 详情 | 详情 |
| (II) | 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 |
| (II) | 44648 | acetyl chloride | 1520-57-6 | C2H3ClO | 详情 | 详情 |
| (III) | 30753 | methyl 5-acetyl-2-hydroxybenzoate | 16475-90-4 | C10H10O4 | 详情 | 详情 |
| (III) | 44649 | methyl 5-acetyl-2-hydroxybenzoate | C10H10O4 | 详情 | 详情 | |
| (IV) | 35836 | methyl 5-(2-bromoacetyl)-2-hydroxybenzoate | C10H9BrO4 | 详情 | 详情 | |
| (IV) | 44650 | methyl 5-(2-bromoacetyl)-2-hydroxybenzoate | C10H9BrO4 | 详情 | 详情 | |
| (V) | 35837 | N-benzyl-6-(4-phenylbutoxy)-1-hexanamine; N-benzyl-N-[6-(4-phenylbutoxy)hexyl]amine | C23H33NO | 详情 | 详情 | |
| (VI) | 35838 | methyl 5-(2-[benzyl[6-(4-phenylbutoxy)hexyl]amino]acetyl)-2-hydroxybenzoate | C33H41NO5 | 详情 | 详情 | |
| (VI) | 44651 | methyl 5-(2-[benzyl[6-(4-phenylbutoxy)hexyl]amino]acetyl)-2-hydroxybenzoate | C33H41NO5 | 详情 | 详情 | |
| (VII) | 35839 | 4-(2-[benzyl[6-(4-phenylbutoxy)hexyl]amino]-1-hydroxyethyl)-2-(hydroxymethyl)phenol | C32H43NO4 | 详情 | 详情 | |
| (VII) | 44652 | 4-(2-[benzyl[6-(4-phenylbutoxy)hexyl]amino]-1-hydroxyethyl)-2-(hydroxymethyl)phenol | C32H43NO4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The condensation of N-benzyl-N-[6-(4-phenylbutoxy)hexyl]amine (I) with 5-(bromoacetyl)salicylaldehyde (II) by means of TEA in isopropanol gives the adduct (III), which is debenzylated and reduced with H2 over Pt/C and Pd/C in ethanol to afford the target triol.
| 【1】 Ariza Aranda, J.; Serra Masià, J.; Montserrat Vidal, C. (Laboratorios Salvat SA); 6-[4-(Phenylbutoxy)]hexylaminomethyl-4-hydroxy-alpha1,alpha3-benzenedimethanol. Process for obtaining it and novel intermediates for its preparation. ES 2065269 . |
| 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) | 35837 | N-benzyl-6-(4-phenylbutoxy)-1-hexanamine; N-benzyl-N-[6-(4-phenylbutoxy)hexyl]amine | C23H33NO | 详情 | 详情 | |
| (II) | 50873 | 5-(2-bromoacetyl)-2-hydroxybenzaldehyde | C9H7BrO3 | 详情 | 详情 | |
| (III) | 50874 | 5-(2-[benzyl[6-(4-phenylbutoxy)hexyl]amino]acetyl)-2-hydroxybenzaldehyde | C32H39NO4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)The condensation of 1,6-dibromohexane (I) with 4-phenyl-1-butanol (II) by means of NaOH under phase transfer catalysis gives 6-(4-phenylbutoxy)hexyl bromide (III), which is condensed with benzylamine (IV) by means of Cs2CO3 in hot DMF to yield the secondary amine (V). The condensation of (V) with methyl alpha-bromo 4-acetylsalicylate (VI) by means of DIEA in refluxing THF affords the tertiary amine (VII), which is submitted to a reductive deuteration by means of deuterated LiAlD4 in THF to provide the trideuterated intermediate (VIII). Finally this compound is deprotected by hydrogenation with H2 over Pd/C in methanol to give rise to the target trideuterated salmeterol.
| 【1】 Molinski, T.F.; Stanley, S.D.; Improved synthesis of 13C,2H3- and 2H3-salmeterol by Cs2CO3-mediated monoalkylation of a primary amine. J Label Compd Radiopharm 2002, 45, 9, 755. |
| 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) | 24786 | 1,6-dibromohexane | 629-03-8 | C6H12Br2 | 详情 | 详情 |
| (II) | 27291 | 4-phenyl-1-butanol | 3360-41-6 | C10H14O | 详情 | 详情 |
| (III) | 31479 | 1-[4-[(6-bromohexyl)oxy]butyl]benzene; 6-bromohexyl-4-phenylbutyl ether; 6-Bromohexyloxybutylbenzene | 94749-73-2 | C16H25BrO | 详情 | 详情 |
| (IV) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (V) | 35836 | methyl 5-(2-bromoacetyl)-2-hydroxybenzoate | C10H9BrO4 | 详情 | 详情 | |
| (VI) | 35837 | N-benzyl-6-(4-phenylbutoxy)-1-hexanamine; N-benzyl-N-[6-(4-phenylbutoxy)hexyl]amine | C23H33NO | 详情 | 详情 | |
| (VII) | 35838 | methyl 5-(2-[benzyl[6-(4-phenylbutoxy)hexyl]amino]acetyl)-2-hydroxybenzoate | C33H41NO5 | 详情 | 详情 | |
| (VIII) | 35839 | 4-(2-[benzyl[6-(4-phenylbutoxy)hexyl]amino]-1-hydroxyethyl)-2-(hydroxymethyl)phenol | C32H43NO4 | 详情 | 详情 | |
| (VIII) | 57250 | 4-(2-{benzyl[6-(4-phenylbutoxy)hexyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol | C32H43NO4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(V)The condensation of 4-phenyl-1-butanol (I) with 1,6-dibromohexane (II) by means of NaH in THF gives the ether (III), which is condensed with benzylamine (IV) by means of NaI and TEA in DMSO to yield the secondary amine (V). The condensation of (V) with 5-(bromoacetyl)-2-hydroxybenzaldehyde (VI) in refluxing acetonitrile affords the tertiary amine (VII). The reduction of both carbonyl groups of (VII) by means of NaBH4 in methanol affords the dihydroxy amine (VIII), which is finally debenzylated by means of h2 over Pd/C in the same solvent to provide the target salmeterol. The intermediate 5-(bromoacetyl)-2-hydroxybenzaldehyde (VI) has been obtained by Friedel Crafts condensation of 2-hydroxybenzaldehyde (IX) with bromoacetyl chloride (X) by means of AlCl3 in dichloromethane.
| 【1】 Rong, Y.; Ruoho, A.E.; A new synthetic approach to salmeterol. Synth Commun 1999, 29, 12, 2155. |
| 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) | 27291 | 4-phenyl-1-butanol | 3360-41-6 | C10H14O | 详情 | 详情 |
| (II) | 24786 | 1,6-dibromohexane | 629-03-8 | C6H12Br2 | 详情 | 详情 |
| (III) | 31479 | 1-[4-[(6-bromohexyl)oxy]butyl]benzene; 6-bromohexyl-4-phenylbutyl ether; 6-Bromohexyloxybutylbenzene | 94749-73-2 | C16H25BrO | 详情 | 详情 |
| (IV) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (V) | 35837 | N-benzyl-6-(4-phenylbutoxy)-1-hexanamine; N-benzyl-N-[6-(4-phenylbutoxy)hexyl]amine | C23H33NO | 详情 | 详情 | |
| (VI) | 50873 | 5-(2-bromoacetyl)-2-hydroxybenzaldehyde | C9H7BrO3 | 详情 | 详情 | |
| (VII) | 50874 | 5-(2-[benzyl[6-(4-phenylbutoxy)hexyl]amino]acetyl)-2-hydroxybenzaldehyde | C32H39NO4 | 详情 | 详情 | |
| (VIII) | 35839 | 4-(2-[benzyl[6-(4-phenylbutoxy)hexyl]amino]-1-hydroxyethyl)-2-(hydroxymethyl)phenol | C32H43NO4 | 详情 | 详情 | |
| (IX) | 21351 | 2-Hydroxybenzaldehyde;Salicylic aldehyde；2-Formylphenol;salicylaldehyde | 90-02-8 | C7H6O2 | 详情 | 详情 |
| (X) | 27903 | 2-Bromoacetyl chloride | 22118-09-8 | C2H2BrClO | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IX)The reaction of 6-(4-phenylbutoxy)hexyl bromide (VI) with NaN3 in DMF gives The azido derivative (VII), which is reduced with LiAlH4 to yield the primary amine (VIII). The reductive alkylation of (VIII) by means of benzaldehyde and NaBH4 affords the benzylamine (IX), which is condensed with the chiral epoxide (V) in refluxing THF to provide the chiral hydroxyamine (X). The reduction of the ester group of (X) with LiAlH4 leads to the hydroxymethyl compound (XI), which is finally fully debenzylated by means of H2 over Pd/C to give rise to the target (R)-salmeterol.
| 【1】 Hett, R.; et al.; Enantioselective synthesis of salmeterol via asymmetric borane reduction. Tetrahedron Lett 1994, 35, 50, 9375. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 62585 | methyl 2-(benzyloxy)-5-[(2R)oxiranyl]benzoate | C17H16O4 | 详情 | 详情 | |
| (VI) | 31479 | 1-[4-[(6-bromohexyl)oxy]butyl]benzene; 6-bromohexyl-4-phenylbutyl ether; 6-Bromohexyloxybutylbenzene | 94749-73-2 | C16H25BrO | 详情 | 详情 |
| (VII) | 62586 | 1-{4-[(6-azidohexyl)oxy]butyl}benzene; 6-azidohexyl 4-phenylbutyl ether | C16H25N3O | 详情 | 详情 | |
| (VIII) | 62577 | 6-(4-phenylbutoxy)-1-hexanamine; 6-(4-phenylbutoxy)hexylamine | C16H27NO | 详情 | 详情 | |
| (IX) | 35837 | N-benzyl-6-(4-phenylbutoxy)-1-hexanamine; N-benzyl-N-[6-(4-phenylbutoxy)hexyl]amine | C23H33NO | 详情 | 详情 | |
| (X) | 62587 | methyl 2-(benzyloxy)-5-((1R)-2-{benzyl[6-(4-phenylbutoxy)hexyl]amino}-1-hydroxyethyl)benzoate | C40H49NO5 | 详情 | 详情 | |
| (XI) | 62588 | (1R)-1-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-{benzyl[6-(4-phenylbutoxy)hexyl]amino}-1-ethanol | C39H49NO4 | 详情 | 详情 |