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【结 构 式】 
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【分子编号】65795 【品名】6-Bromo-2-chloro-3-(phenylmethyl)quinoline 【CA登记号】654655-68-2 |
【 分 子 式 】C16H11BrClN 【 分 子 量 】332.62678 【元素组成】C 57.78% H 3.33% Br 24.02% Cl 10.66% N 4.21% |
合成路线1
该中间体在本合成路线中的序号：(IV)Condensation of 4-bromoaniline (I) with 3-phenylpropionyl chloride (II) by means of triethylamine in dichloromethane gives the propionamide (III), which is cyclized with dimethylformamide by means of POCl3 in hot DMF to yield 3-benzyl-6-bromo-2-chloroquinoline (IV). Reaction of compound (IV) with NaOMe in refluxing methanol affords the 2-methoxyquinoline derivative (V), which is condensed with 3-(dimethylamino)-1-(1-naphthyl)propanone (VI) by means of BuLi in THF to provide a mixture of two diastereomeric racemates (R*,R*/R*,S*) (VII) that are separated by column chromatography. Finally, the desired (R*,S*)-racemic mixture is submitted to chiral chromatography (1). Scheme 1.
In an improved process, 3-benzyl-6-bromo-2-methoxyquinoline (V) is condensed with 3-(dimethylamino)-1-(1-naphthyl)propanone (VI) by means of LDA in THF and then treated with AcOH to afford the tertiary alcohol (VII). Finally, alcohol (VII) is submitted to optical resolution by crystallization with chiral 4-hydroxydinaphtho[2,1-d:1’,2’-f][1,3,2]dioxaphosphepin 4-oxide (2). Scheme 1.
| 【1】 Van Gestel, J.F.E., Venet, M.G., Vernier, D.F.J., Decrane, L.F.B., Poignet, H.J.J. (Janssen Pharmaceutica NV). Quinoline derivatives and their use as mycobacterial inhibitors. CA 2493225, EP 1527050, JP 2006504658, WO 2004011436. |
| 【2】 Porstmann, F.R., Horns, S., Bader, T. (Janssen Pharmaceutica NV). Process for preparing (alphaS,betaR)-6-bromo-alpha-[2-(dimethylamino)ethyl]-2-methoxy-alpha-1-naphthalenyl-beta-phenyl-3-quinolineethanol. CA 2606675, EP 1888604, US 2008200683, WO 2006125769. |
| 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) | 22531 | 4-Bromoaniline; 4-Bromophenylamine | 106-40-1 | C6H6BrN | 详情 | 详情 |
| (II) | 16240 | 3-phenylpropanoyl chloride; Hydrocinnamoylchloride | 645-45-4 | C9H9ClO | 详情 | 详情 |
| (III) | 65794 | N-(4-Bromophenyl)-3-Phenylpropanamide | 316146-27-7 | C15H14BrNO | 详情 | 详情 |
| (IV) | 65795 | 6-Bromo-2-chloro-3-(phenylmethyl)quinoline | 654655-68-2 | C16H11BrClN | 详情 | 详情 |
| (V) | 65796 | 3-Benzyl-6-bromo-2-methoxyquinoline | 654655-69-3 | C17H14BrNO | 详情 | 详情 |
| (VI) | 65797 | 3-(Dimethylamino)-1-(naphthalen-1-yl)propan-1-one; (2-alpha-Naphthoylethyl)dimethylamine; 2-(Dimethylamino)ethyl 1-naphthyl ketone | 10320-49-7 | C15H17NO | 详情 | 详情 |
| (VII) | 65798 | 6-Bromo-alpha-[2-(dimethylamino)ethyl]-2-methoxy-alpha-1-naphthalenyl-beta-phenyl-3-quinolineethanol | 654655-80-8 | C32H31BrN2O2 | 详情 | 详情 |