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【结 构 式】 
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【分子编号】31479 【品名】1-[4-[(6-bromohexyl)oxy]butyl]benzene; 6-bromohexyl-4-phenylbutyl ether; 6-Bromohexyloxybutylbenzene 【CA登记号】94749-73-2 |
【 分 子 式 】C16H25BrO 【 分 子 量 】313.2779 【元素组成】C 61.34% H 8.04% Br 25.51% O 5.11% |
合成路线1
该中间体在本合成路线中的序号：(III)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：(III)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：(III)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：(III)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：(V)The reaction of 6-(4-phenylbutoxy)hexanol methanesulfonate (I) with (R)-phenylglycinol (II) by means of DIEA and NaI in hot acetonitrile gives the secondary amine (III), which is condensed with 2-(benzyloxy)-5-(2-bromoacetyl)benzoic acid methyl ester (IV) by means of DIEA in refluxing 1,2-dimethoxyethane to yield the tertiary amine (V). The enantioselective reduction of (V) with LiBH4 in refluxing dimethoxyethane affords the tetrahydroxy derivative (VI), which is finally debenzylated by hydrogenation with H2 over Pd/C in ethanol to provide the target aminoethanol derivative.
| 【1】 Procopiou, P.A. (GlaxoSmithKline plc); A novel process for preparing salmeterol. WO 0196278 . |
| 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) | 52359 | 2-bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1-ethanone | C12H13BrO3 | 详情 | 详情 | |
| (II) | 10973 | (2S)-2-Amino-2-phenyl-1-ethanol; (S)-2-Hydroxy-1-phenylethylamine; (S)-(+)-2-Phenylglycinol; (S)-2-Amino-2-phenyl-1-ethanol | 20989-17-7 | C8H11NO | 详情 | 详情 |
| (III) | 52360 | 1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-[(2-hydroxy-1-phenylethyl)amino]-1-ethanone | C20H23NO4 | 详情 | 详情 | |
| (IV) | 52361 | (1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-{[(1S)-2-hydroxy-1-phenylethyl]amino}-1-ethanol | C20H25NO4 | 详情 | 详情 | |
| (V) | 31479 | 1-[4-[(6-bromohexyl)oxy]butyl]benzene; 6-bromohexyl-4-phenylbutyl ether; 6-Bromohexyloxybutylbenzene | 94749-73-2 | C16H25BrO | 详情 | 详情 |
| (VI) | 52362 | 6-[(4-phenylbutyl)oxy]hexanal | C16H24O2 | 详情 | 详情 | |
| (VII) | 52363 | (1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-{[(1S)-2-hydroxy-1-phenylethyl][6-(4-phenylbutoxy)hexyl]amino}-1-ethanol | C36H49NO5 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(VI)The condensation of the phenacyl bromide (I) with the chiral auxiliary (II) by means of DIEA in THF gives the chiral secondary amine (III), which is submitted to a diastereoselective reduction of the carbonyl group by means of CaCl2 and NaBH4 in methanol to yield a 10:1 enriched mixture of the desired (R)-enantiomer (IV), easily separated by crystallization. The reductocondensation of the chiral amine (IV) with 6-(4-phenylbutoxy)hexanal (V) (obtained by oxidation of 6-(4-phenylbutoxy)hexyl bromide (VI) by means of NaHCO3 and DMSO at 150 C) by means of NaBH(OAc)3 in dichloromethane affords the tertiary amine (VII). Elimination of the chiral auxiliary of (VII) by means of H2 over Pd/C in ethanol provides the secondary amine (VIII), which is finally passed through an acidic SCX-2 ion exchange resin in ethanol to eliminate the acetonide group and give rise to the target (R)-salmeterol.
| 【1】 Bream, R.N.; et al.; A mild, enantioselective synthesis of (R)-salmeterol via sodium borohydride-calcium chloride asymmetric reduction of a phenacyl phenylglycinol derivative. J Chem Soc - Perkins Trans I 2002, 20, 2237. |
| 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) | 10973 | (2S)-2-Amino-2-phenyl-1-ethanol; (S)-2-Hydroxy-1-phenylethylamine; (S)-(+)-2-Phenylglycinol; (S)-2-Amino-2-phenyl-1-ethanol | 20989-17-7 | C8H11NO | 详情 | 详情 |
| (I) | 52359 | 2-bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1-ethanone | C12H13BrO3 | 详情 | 详情 | |
| (III) | 52360 | 1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-[(2-hydroxy-1-phenylethyl)amino]-1-ethanone | C20H23NO4 | 详情 | 详情 | |
| (IV) | 52361 | (1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-{[(1S)-2-hydroxy-1-phenylethyl]amino}-1-ethanol | C20H25NO4 | 详情 | 详情 | |
| (V) | 52362 | 6-[(4-phenylbutyl)oxy]hexanal | C16H24O2 | 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) | 52363 | (1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-{[(1S)-2-hydroxy-1-phenylethyl][6-(4-phenylbutoxy)hexyl]amino}-1-ethanol | C36H49NO5 | 详情 | 详情 | |
| (VIII) | 52679 | (1R)-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7
该中间体在本合成路线中的序号：(VI)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 |
合成路线8
该中间体在本合成路线中的序号：(VII)The condensation of bromoketone (I) with di-tert-butyl iminodicarboxylate (II) by means of Cs2CO3 in acetonitrile gives the adduct (III), which is monodecarboxylated by reaction with TFA in dichloromethane to yield the carbamate (IV). The asymmetric reduction of the ketonic group of (IV) by means of BH3 and a chiral oxazaborole catalyst affords the (R)-alcohol (V), which is cyclized by means of NaH in DMF to provide the chiral oxazolidinone (VI). The alkylation of (VI) with 6-(4-phenylbutoxy)hexyl bromide (VII) by means of NaH in THF gives the alkylated oxazolidinone (VIII), which is treated with Tms-OK in THF to cleave the oxazolidinone ring, yielding the aminoalcohol (IX). Finally, the acetonide ring of (IX) is cleaved by means of AcOH in methanol to provide salmeterol.
| 【1】 Coe, D.M.; Perciaccante, R.; Procopiou, P.A.; Potassium trimethylsilanolate induced cleavage of 1,3-oxazolidin-2 and 5-ones, and application to the synthesis of (R)-salmeterol. Org Biomol Chem 2003, 1, 7, 1106. |
| 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) | 52359 | 2-bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1-ethanone | C12H13BrO3 | 详情 | 详情 | |
| (II) | 48447 | Di-tert-butyl iminodicarboxylate; Iminodicarboxylic acid di-tert-butyl ester | 51779-32-9 | C10H19NO4 | 详情 | 详情 |
| (III) | 64766 | 6-{2-[bis(tert-butoxycarbonyl)amino]acetyl}-2,2-dimethyl-4H-1,3-benzodioxine | C22H31NO7 | 详情 | 详情 | |
| (IV) | 64767 | tert-butyl 2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethylcarbamate | C17H23NO5 | 详情 | 详情 | |
| (V) | 64768 | tert-butyl (2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethylcarbamate | C17H25NO5 | 详情 | 详情 | |
| (VI) | 64769 | (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one | C13H15NO4 | 详情 | 详情 | |
| (VII) | 31479 | 1-[4-[(6-bromohexyl)oxy]butyl]benzene; 6-bromohexyl-4-phenylbutyl ether; 6-Bromohexyloxybutylbenzene | 94749-73-2 | C16H25BrO | 详情 | 详情 |
| (VIII) | 64770 | (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-3-[6-(4-phenylbutoxy)hexyl]-1,3-oxazolidin-2-one | C29H39NO5 | 详情 | 详情 | |
| (IX) | 52679 | (1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-{[6-(4-phenylbutoxy)hexyl]amino}-1-ethanol | C28H41NO4 | 详情 | 详情 |