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【结 构 式】 
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【药物名称】(-)-Salmeterol, (R)-Salmeterol 【化学名称】(R)-(-)-2-(Hydroxymethyl)-4-[1-hydroxy-2-[6-(4-phenylbutoxy)hexylamino]ethyl]phenol 【CA登记号】135271-47-5 【 分 子 式 】C25H37NO4 【 分 子 量 】415.57794 |
【开发单位】GlaxoSmithKline (Originator) 【药理作用】Antiallergy/Antiasthmatic Drugs, Asthma Therapy, Bronchodilators, RESPIRATORY DRUGS, beta2-Adrenoceptor Agonists |
合成路线1
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】 Evans, B. (GlaxoSmithKline plc); Phenethanolamine cpds.. AU 9163901; EP 0422889; JP 1991133946 . |
| 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) | 52354 | 6-[(4-phenylbutyl)oxy]hexyl methanesulfonate | C17H28O4S | 详情 | 详情 | |
| (II) | 14376 | (2R)-2-amino-2-phenyl-1-ethanol; (R)-(-)-2-phenylglycinol; (R)-2-amino-2-phenyl-1-ethanol | 56613-80-0 | C8H11NO | 详情 | 详情 |
| (III) | 52355 | 2-phenyl-2-({6-[(4-phenylbutyl)oxy]hexyl}amino)-1-ethanol | C24H35NO2 | 详情 | 详情 | |
| (IV) | 52356 | methyl 5-(2-bromoacetyl)-2-[(phenylmethyl)oxy]benzoate | C17H15BrO4 | 详情 | 详情 | |
| (V) | 52357 | methyl 5-[2-((2-hydroxy-1-phenylethyl){6-[(4-phenylbutyl)oxy]hexyl}amino)acetyl]-2-[(phenylmethyl)oxy]benzoate | C41H49NO6 | 详情 | 详情 | |
| (VI) | 52358 | (1R)-1-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-{[(1R)-2-hydroxy-1-phenylethyl][6-(4-phenylbutoxy)hexyl]amino}-1-ethanol | C40H51NO5 | 详情 | 详情 |
合成路线2
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3
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4
The enantioselective reduction of the phenacyl bromide (I) by means of a culture of Rhodotolule rubra in water gives the a(R)-hydroxy enantiomer (II), which is treated with K2CO3 in refluxing ethanol to yield the chiral epoxide (III). The condensation of (III) with 6-(4-phenylbutoxy)hexylamine (IV) by means of N,O-bis(trimethylsilyl)acetamide (TMSA) in hot DMSO affords the precursor (V), which is finally deprotected by means of HCl in water to provide the target (R)-salmeterol.
| 【1】 Goswami, J.; et al.; A conventient stereoselective synthesis of (R)-(-)-denopamine and (R)-(-)-salmeterol. Tetrahedron Asymmetry 2001, 12, 24, 3343. |
| 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) | 62574 | 1-(4H-1,3-benzodioxin-6-yl)-2-bromo-1-ethanone | C10H9BrO3 | 详情 | 详情 | |
| (II) | 62575 | (1R)-1-(4H-1,3-benzodioxin-6-yl)-2-bromo-1-ethanol | C10H11BrO3 | 详情 | 详情 | |
| (III) | 62576 | 6-[(2R)oxiranyl]-4H-1,3-benzodioxine | C10H10O3 | 详情 | 详情 | |
| (IV) | 62577 | 6-(4-phenylbutoxy)-1-hexanamine; 6-(4-phenylbutoxy)hexylamine | C16H27NO | 详情 | 详情 | |
| (V) | 62578 | (1R)-1-(4H-1,3-benzodioxin-6-yl)-2-{[6-(4-phenylbutoxy)hexyl]amino}-1-ethanol | C26H37NO4 | 详情 | 详情 |
合成路线5
The enantioselective reduction of the phenacyl bromide (I) by means of a culture of Rhodotolule rubra in water gives the a(R)-hydroxy enantiomer (II), which is treated with K2CO3 in refluxing ethanol to yield the chiral epoxide (III). The condensation of (III) with 6-(4-phenylbutoxy)hexylamine (IV) by means of N,O-bis(trimethylsilyl)acetamide (TMSA) in hot DMSO affords the benzylated precursor (V), which is finally deprotected by means of H2,Pd/C in water to provide the target (R)-salmeterol.
| 【1】 Goswami, J.; et al.; A conventient stereoselective synthesis of (R)-(-)-denopamine and (R)-(-)-salmeterol. Tetrahedron Asymmetry 2001, 12, 24, 3343. |
| 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) | 62579 | 1-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-bromo-1-ethanone | C16H15BrO3 | 详情 | 详情 | |
| (II) | 62580 | (1R)-1-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-bromo-1-ethanol | C16H17BrO3 | 详情 | 详情 | |
| (III) | 62581 | {2-(benzyloxy)-5-[(2R)oxiranyl]phenyl}methanol | C16H16O3 | 详情 | 详情 | |
| (IV) | 62577 | 6-(4-phenylbutoxy)-1-hexanamine; 6-(4-phenylbutoxy)hexylamine | C16H27NO | 详情 | 详情 | |
| (V) | 62582 | (1R)-1-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-{[6-(4-phenylbutoxy)hexyl]amino}-1-ethanol | C32H43NO4 | 详情 | 详情 |
合成路线6
The intermediate chiral epoxide (V) has been obtained as follows: The bromination of 5-acetyl-2-benzyloxybenzoic acid methyl ester (I) with Br2 in chloroform gives the bromoacetyl derivative (II), which is submitted to a enantioselective reduction by means of BH3/THF catalyzed by the chiral oxazaborolidine (III) to yield the (R)-enantiomer (IV). Finally, this compound is cyclized by means of NaH in THF to afford the target (R)-epoxide (
| 【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 |
|---|---|---|---|---|---|---|
| (I) | 62583 | methyl 5-acetyl-2-(benzyloxy)benzoate | C17H16O4 | 详情 | 详情 | |
| (II) | 52356 | methyl 5-(2-bromoacetyl)-2-[(phenylmethyl)oxy]benzoate | C17H15BrO4 | 详情 | 详情 | |
| (III) | 20631 | (R)-Methyl oxazaborolidine; (3aR)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole | 112022-83-0 | C18H20BNO | 详情 | 详情 |
| (IV) | 62584 | methyl 2-(benzyloxy)-5-[(1R)-2-bromo-1-hydroxyethyl]benzoate | C17H17BrO4 | 详情 | 详情 | |
| (V) | 62585 | methyl 2-(benzyloxy)-5-[(2R)oxiranyl]benzoate | C17H16O4 | 详情 | 详情 |
合成路线7
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
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 |