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【结 构 式】 
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【分子编号】27291 【品名】4-phenyl-1-butanol 【CA登记号】3360-41-6 |
【 分 子 式 】C10H14O 【 分 子 量 】150.22056 【元素组成】C 79.96% H 9.39% O 10.65% |
合成路线1
该中间体在本合成路线中的序号：(I)The reaction of 4-phenyl-1-butanol (I) with 1,6-dibromohexane by means of NaH in THF gives the ether derivative (III), which is then condensed with 5-(2-amino-1-hydroxyethyl)-2-hydroxybenzyl alcohol (IV) by means of KI and triethylamine in hot DMF.
| 【1】 Skidmore, I.F.; Lunts, L.H.C.; Finch, H.; Naylor, A. (Glaxo Group Ltd.); Phenethanolamine derivs. BE 0899448; DE 3414752; ES 8609209; FR 2545482; GB 2140800; GB 2176476; JP 1988264443; JP 1994087800; US 4992474; US 5091422 . |
| 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) | 31480 | 4-(2-amino-1-hydroxyethyl)-2-(hydroxymethyl)phenol | C9H13NO3 | 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 reaction of 4-phenyl-1-butanol (I) with 1,6-dibromohexane (II) by means of KOH and tetrabutylammonium bisulfate gives the butyl hexyl ether (III), which is condensed with 2-aminoacetaldehyde dimethylacetal (IV) in refluxing toluene yielding 2-[6-(4-phenylbutoxy)hexylamino]acetaldehyde dimethylacetal (V). The protection of the amino group of (V) with N-(benzyloxycarbonyloxy)succinimide and triethylamine in acetone affords the carbamate (VI), which is treated with TsOH in acetone to provide the acetaldehyde derivative (VII). The condensation of (VII) with 6-bromo-2,2-dimethyl-1,3-benzodioxan (VIII) (obtained by cyclization of phenol (IX) with acetone and AlCl3) by means of Mg in THF gives the expected carbinol (X), which is deprotected with H2 over Pd/C in methanol yielding the aminoethanol derivative (XI). Finally, this compound is treated with HCl in methanol/water to open the 1,3-dioxane ring and afford the target compound.
| 【1】 Marquillas Olondriz, F.; Dalmases Barjoan, P.; Bessa Bellmunt, J. (Laboratorios Vita, SA); New derivs. of 6-(4-phenylbutoxy)hexylamine and process for producing salmeterol. ES 2142771; WO 0018722 . |
| 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) | 34158 | aminoacetaldehyde dimethylacetal; 2,2-dimethoxy-1-ethanamine; 2,2-dimethoxyethylamine | 22483-09-6 | C4H11NO2 | 详情 | 详情 |
| (V) | 36932 | N-(2,2-dimethoxyethyl)-N-[6-(4-phenylbutoxy)hexyl]amine; N-(2,2-dimethoxyethyl)-6-(4-phenylbutoxy)-1-hexanamine | C20H35NO3 | 详情 | 详情 | |
| (VI) | 36933 | benzyl 2,2-dimethoxyethyl[6-(4-phenylbutoxy)hexyl]carbamate | C28H41NO5 | 详情 | 详情 | |
| (VII) | 36934 | benzyl 2-oxoethyl[6-(4-phenylbutoxy)hexyl]carbamate | C26H35NO4 | 详情 | 详情 | |
| (VIII) | 36935 | 4-bromo-2-(hydroxymethyl)phenol | 2316-64-5 | C7H7BrO2 | 详情 | 详情 |
| (IX) | 36936 | 6-bromo-2,2-dimethyl-4H-1,3-benzodioxine | C10H11BrO2 | 详情 | 详情 | |
| (X) | 36937 | benzyl 2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl[6-(4-phenylbutoxy)hexyl]carbamate | C36H47NO6 | 详情 | 详情 | |
| (XI) | 36938 | 1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-[[6-(4-phenylbutoxy)hexyl]amino]-1-ethanol | C28H41NO4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)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：(I)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：(VII)4-Bromophenol (I) was acetylated with Ac2O and Et3N, and the resulting 4-bromophenyl acetate (II) was rearranged to 5'-bromo-2'-hydroxyacetophenone (III) in the presence of AlCl3 at 120 C. Subsequent nitration of (III) produced the 3'-nitroacetophenone (IV). The catalytic hydrogenation of the nitro group of (IV), with simultaneous halogen hydrogenolysis, furnished 3'-amino-2'-hydroxyacetophe-none (V). Then, diazotization of the amine group of (V), followed by treatment with KI and Cu powder gave iodide (VI). Coupling of 4-phenyl-1-butanol (VII) with 4-hydroxybenzaldehyde (VIII) under Mitsunobu conditions provided 4-(4-phenylbutoxy)benzaldehyde (IX). Further Wittig reaction of (IX) with methylene triphenylphosphorane (X) gave the styrene (XI). This was condensed with the iodoacetophenone (VI) in the presence of Pd(OAc)2 to produce the stilbene derivative (XII). The benzopyranone (XIII) was prepared by condensation of hydroxyacetophenone (XII) with diethyl oxalate in the presence of NaOEt, followed by acid cyclization. After conversion of the ester function of (XIII) to the corresponding amide with methanolic ammonia, dehydration using POCl3 in DMF afforded nitrile (XIV). The required tetrazole ring was finally obtained by reaction with NaN3 and NH4Cl in DMF at 100 C.
| 【1】 Carganico, G.; Mauleon Casellas, D.; Pascual Avellana, J.; Garcia Perez, M.L.; Palomer Benet, A. (Menarini Industrie Farma Riunite srl); Benzopyran derivs. having leukotriene-antagonistic action. EP 0888327; ES 2127106; JP 2000506878; US 5990142; WO 9734885 . |
| 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) | 25313 | 4-bromophenol | 106-41-2 | C6H5BrO | 详情 | 详情 |
| (II) | 27286 | 4-bromophenyl acetate | C8H7BrO2 | 详情 | 详情 | |
| (III) | 27287 | 1-(5-bromo-2-hydroxyphenyl)-1-ethanone | 1450-75-5 | C8H7BrO2 | 详情 | 详情 |
| (IV) | 27288 | 1-(5-bromo-2-hydroxy-3-nitrophenyl)-1-ethanone | C8H6BrNO4 | 详情 | 详情 | |
| (V) | 27289 | 1-(3-amino-2-hydroxyphenyl)-1-ethanone | C8H9NO2 | 详情 | 详情 | |
| (VI) | 27290 | 1-(2-hydroxy-3-iodophenyl)-1-ethanone | C8H7IO2 | 详情 | 详情 | |
| (VII) | 27291 | 4-phenyl-1-butanol | 3360-41-6 | C10H14O | 详情 | 详情 |
| (VIII) | 13433 | 4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde | 123-08-0 | C7H6O2 | 详情 | 详情 |
| (IX) | 27292 | 4-(4-phenylbutoxy)benzaldehyde | C17H18O2 | 详情 | 详情 | |
| (X) | 27301 | methylene(triphenyl)phosphorane | C19H17P | 详情 | 详情 | |
| (XI) | 27293 | 1-(4-phenylbutoxy)-4-vinylbenzene | C18H20O | 详情 | 详情 | |
| (XII) | 27294 | 1-(2-hydroxy-3-[(E)-2-[4-(4-phenylbutoxy)phenyl]ethenyl]phenyl)-1-ethanone | C26H26O3 | 详情 | 详情 | |
| (XIII) | 27295 | ethyl 4-oxo-8-[(E)-2-[4-(4-phenylbutoxy)phenyl]ethenyl]-4H-chromene-2-carboxylate | C30H28O5 | 详情 | 详情 | |
| (XIV) | 27296 | 4-oxo-8-[(E)-2-[4-(4-phenylbutoxy)phenyl]ethenyl]-4H-chromene-2-carbonitrile | C28H23NO3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)Treatment of 4-phenylbutanol (I) with PBr3 gave the corresponding bromide (II). 6-Methoxytryptamine (III) was converted to the hydrochloride salt, and then condensed with formaldehyde under Pictet-Spengler conditions to furnish the pyridoindole system (IV). Alkylation of amine (IV) with bromide (II) then gave the phenylbutyl amine (V). Finally, O-demethylation of (V) employing BBr3 yielded the title compound.
| 【1】 Becker, R.E.; Thornton, S.L.; Moriearty, P.L.; Transdermal patch delivery of acetylcholinesterase inhibitors. Methods Find Exp Clin Pharmacol 1993, 15, 6, 407. |
| 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) | 27300 | 1-(4-bromobutyl)benzene; (4-bromobutyl)benzene | 13633-25-5 | C10H13Br | 详情 | 详情 |
| (III) | 35822 | 6-Methoxytryptamine; 3-(2-Aminoethyl)-6-methoxyindole; 2-(6-Methoxy-1H-indol-3-yl)-1-ethanamine; 2-(6-Methoxy-1H-indol-3-yl)ethylamine | 3610-36-4 | C11H14N2O | 详情 | 详情 |
| (IV) | 35823 | 7-methoxy-2,3,4,9-tetrahydro-1H-beta-carboline; methyl 2,3,4,9-tetrahydro-1H-beta-carbolin-7-yl ether | C12H14N2O | 详情 | 详情 | |
| (V) | 35824 | 7-methoxy-2-(4-phenylbutyl)-2,3,4,9-tetrahydro-1H-beta-carboline; methyl 2-(4-phenylbutyl)-2,3,4,9-tetrahydro-1H-beta-carbolin-7-yl ether | C22H26N2O | 详情 | 详情 |