【结 构 式】 |
【分子编号】16998 【品名】6-bromo-4-oxo-1,2,3,4-tetrahydro-1-naphthalenecarboxylic acid 【CA登记号】 |
【 分 子 式 】C11H9BrO3 【 分 子 量 】269.09466 【元素组成】C 49.1% H 3.37% Br 29.69% O 17.84% |
合成路线1
该中间体在本合成路线中的序号:(XVII)Tritium-labeled RS-25259-197 can be obtained by the reaction of methyl 4-bromophenylacetate (XI) with methyl chloroformate (XII) by means of lithium diisopropylamide (LDA) in THF, giving the malonic ester (XIII), which is condensed with methyl acrylate (XIV) by means of Na in methanol to yield the tricarboxylic ester (XV). The decarboxylative hydrolysis of (XV) first with NaOH and finally in acidic medium (HCl) affords 2-(4-bromophenyl)glutaric acid (XVI), which is cyclized with hot polyphosphoric acid (PPA) to give 6-bromo-4-oxo-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (XVII). The reduction of (XVII) with NaBH4 in isopropanol yields the corresponding hydroxy acid (XVIII), which is dehydrated with p-toluenesulfonic acid to the lactone (XIX). Isomerization of (XIX) with H3PO4 in THF affords 6-bromo-1,2-dihydronaphthalene-1-carboxylic acid (XX), which is condensed with quinuclidin-3(S)-ylamine (III) by means of dicyclohexylcarbodiimide (DCC) and hydroxybenzotriazole (HOBT) in acetonitrile to give the corresponding amide as a mixture of diastereomers that is resolved by chromatography and crystallization in order to obtain the (S,S)-isomer (XXI). The hydrogenation of (XXI) with tritium (3H2) and Pd/C in ethyl acetate affords (S,S)-N-(3-quinuclidinyl)-3,4,7-tri-3H-1,2,3,4-tetrahydronaphthalene-1-carboxamide (XXII), which is reduced with the complex borane.dimethylsulfide to the corresponding amine (XXIII). Finally, this compound is cyclized with trichloromethyl chloroformate (diphosgene) in refluxing toluene.
【1】 Graul, A.; Castañer, J.; RS-25259-197. Drugs Fut 1996, 21, 9, 906. |
【2】 Gong, L.; Parnes, H.; Synthesis of the 3H-labelled 5-HT3 antagonist (RS-25259-197) at high specific activity. J Label Compd Radiopharm 1996, 38, 5, 425. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(III) | 16984 | (3S)-1-azabicyclo[2.2.2]octan-3-amine; 1-aza-Bicyclo[2.2.2]oct-3-ylamine; (3S)-1-azabicyclo[2.2.2]oct-3-ylamine | 120570-05-0 | C7H14N2 | 详情 | 详情 |
(XI) | 16992 | methyl 2-(4-bromophenyl)acetate | 41841-16-1 | C9H9BrO2 | 详情 | 详情 |
(XII) | 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester;[(chlorocarbonyl)oxy]methane;methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 |
(XIII) | 16994 | dimethyl 2-(4-bromophenyl)malonate | C11H11BrO4 | 详情 | 详情 | |
(XIV) | 14156 | methyl acrylate | 96-33-3 | C4H6O2 | 详情 | 详情 |
(XV) | 16996 | trimethyl 1-(4-bromophenyl)-1,1,3-propanetricarboxylate | C15H17BrO6 | 详情 | 详情 | |
(XVI) | 16997 | 2-(4-bromophenyl)pentanedioic acid | C11H11BrO4 | 详情 | 详情 | |
(XVII) | 16998 | 6-bromo-4-oxo-1,2,3,4-tetrahydro-1-naphthalenecarboxylic acid | C11H9BrO3 | 详情 | 详情 | |
(XVIII) | 16999 | 6-bromo-4-hydroxy-1,2,3,4-tetrahydro-1-naphthalenecarboxylic acid | C11H11BrO3 | 详情 | 详情 | |
(XIX) | 17000 | 5-bromo-9-oxatricyclo[6.2.2.0(2,7)]dodeca-2,4,6-trien-10-one | C11H9BrO2 | 详情 | 详情 | |
(XX) | 17001 | 6-bromo-1,2-dihydro-1-naphthalenecarboxylic acid | C11H9BrO2 | 详情 | 详情 | |
(XXI) | 17002 | (1S)-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1,2-dihydro-1-naphthalenecarboxamide | C18H21BrN2O | 详情 | 详情 | |
(XXII) | 17003 | (1S)-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,2,3,4-tetrahydro-1-naphthalenecarboxamide | C18H24N2O | 详情 | 详情 | |
(XXII) | 45319 | (1S)-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,2,3,4-tetrahydro-1-naphthalenecarboxamide | C18H24N2O | 详情 | 详情 | |
(XXIII) | 17004 | (3S)-N-[(1S)-1,2,3,4-tetrahydro-1-naphthalenylmethyl]-1-azabicyclo[2.2.2]octan-3-amine; N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-N-[(1S)-1,2,3,4-tetrahydro-1-naphthalenylmethyl]amine | C18H26N2 | 详情 | 详情 | |
(XXIII) | 45320 | N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-N-[(1S)-1,2,3,4-tetrahydro-1-naphthalenylmethyl]amine; (3S)-N-[(1S)-1,2,3,4-tetrahydro-1-naphthalenylmethyl]-1-azabicyclo[2.2.2]octan-3-amine | C18H26N2 | 详情 | 详情 |