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【结 构 式】

【分子编号】52360

【品名】1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-[(2-hydroxy-1-phenylethyl)amino]-1-ethanone

【CA登记号】

【 分 子 式 】C20H23NO4

【 分 子 量 】341.40696

【元素组成】C 70.36% H 6.79% N 4.1% O 18.75%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(III)

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2

该中间体在本合成路线中的序号:(III)

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
Extended Information