1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-[(2-hydroxy-1-phenylethyl)amino]-1-ethanone -Drug Synthesis Database

【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 合成路线2

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.

参考文献中间体

合成目标

【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.

参考文献中间体

合成目标

【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