methyl 5-(2-bromoacetyl)-2-hydroxybenzoate -Drug Synthesis Database

【结构式】

【分子编号】35836

【品名】methyl 5-(2-bromoacetyl)-2-hydroxybenzoate

【CA登记号】

【分子式】C₁₀H₉BrO₄

【分子量】273.08306

【元素组成】C 43.98% H 3.32% Br 29.26% O 23.44%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(IV)

The Friedel-Crafts condensation of 2-hydroxybenzoic acid methyl ester (I) with 13C-labeled acetyl chloride (II) by means of AlCl3 in dichloromethane gives 5-acetyl-2-hydroxybenzoic acid methyl ester (III), which is brominated with Br2 in CHCl3 yielding the bromoacetyl compound (IV). The condensation of (IV) with the secondary amine (V) by means of DIEA in THF affords the tertiary amine (VI), which is reduced with LiAlD4 in refluxing ethyl ether to provide the trideuterated triol (VII). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in ethanol.

参考文献中间体

合成目标

【1】 Goodwin, T.E.; et al.; Synthesis of 13C,2H3-salmeterol: An analytical internal standard for pharmacokinetic studies. J Label Compd Radiopharm 2000, 43, 1, 65.

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)	15754	methyl salicylate	119-36-8	C₈H₈O₃	详情	详情
(II)	19273	acetyl chloride	75-36-5	C₂H₃ClO	详情	详情
(II)	44648	acetyl chloride	1520-57-6	C₂H₃ClO	详情	详情
(III)	30753	methyl 5-acetyl-2-hydroxybenzoate	16475-90-4	C₁₀H₁₀O₄	详情	详情
(III)	44649	methyl 5-acetyl-2-hydroxybenzoate		C₁₀H₁₀O₄	详情	详情
(IV)	35836	methyl 5-(2-bromoacetyl)-2-hydroxybenzoate		C₁₀H₉BrO₄	详情	详情
(IV)	44650	methyl 5-(2-bromoacetyl)-2-hydroxybenzoate		C₁₀H₉BrO₄	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)	35838	methyl 5-(2-[benzyl[6-(4-phenylbutoxy)hexyl]amino]acetyl)-2-hydroxybenzoate		C₃₃H₄₁NO₅	详情	详情
(VI)	44651	methyl 5-(2-[benzyl[6-(4-phenylbutoxy)hexyl]amino]acetyl)-2-hydroxybenzoate		C₃₃H₄₁NO₅	详情	详情
(VII)	35839	4-(2-[benzyl[6-(4-phenylbutoxy)hexyl]amino]-1-hydroxyethyl)-2-(hydroxymethyl)phenol		C₃₂H₄₃NO₄	详情	详情
(VII)	44652	4-(2-[benzyl[6-(4-phenylbutoxy)hexyl]amino]-1-hydroxyethyl)-2-(hydroxymethyl)phenol		C₃₂H₄₃NO₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(V)

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.

参考文献中间体

合成目标

【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3

该中间体在本合成路线中的序号：(I)

The reaction of methyl 5-bromoacetylsalicylate (I) with benzyl tert-butylamine (II) in methyl ethyl ketone gives methyl 5-(N-benzyl-N-tert-butyl-gycyl)salicylate (III), which is reduced with LiAlH4 in refluxing THF yielding alpha'-(N-benzyl-N-tert-butylami-nomethyl)-4-hydroxy-m-xylene-alpha,alpha'-diol (IV). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in ethanol-water.

参考文献中间体

合成目标

【1】 Castaner, J.; Blancafort, P.; Serradell, M.N.; Hopkins, S.J.; Albuterol. Drugs Fut 1979, 4, 9, 629.
【2】 Lunts, L.H.C.; et al.; GB 1200886 .

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)	35836	methyl 5-(2-bromoacetyl)-2-hydroxybenzoate		C₁₀H₉BrO₄	详情	详情
(II)	24700	N-benzyl-2-methyl-2-propanamine	3378-72-1	C₁₁H₁₇N	详情	详情
(III)	39613	methyl 5-[2-[benzyl(tert-butyl)amino]acetyl]-2-hydroxybenzoate		C₂₁H₂₅NO₄	详情	详情
(IV)	39614	4-[2-[benzyl(tert-butyl)amino]-1-hydroxyethyl]-2-(hydroxymethyl)phenol		C₂₀H₂₇NO₃	详情	详情

Extended Information