反応 #44129

反応方程式

thionyl chloride

trimethylaluminium

3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline

3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline

7-fluoro-2-benzofuran-1(3H)-one

→

2-(chloromethyl)-6-fluoro-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide

溶媒

dichloromethane

DCM

反応条件

後処理

1. 1
   workup.STIRRINGThe solution was stirred for 2 h at 0° C.
2. 2
   その他then partitioned between saturated aqueous ammonium chloride solution and ethyl acetate
3. 3
   乾燥The organic phase was dried over sodium sulfate
4. 4
   濃縮concentrated under reduced pressure
5. 5
   workup.DISSOLUTIONThe crude 2-fluoro-6-(hydroxymethyl)-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide was dissolved in DCM and to 0° C
6. 6
   workup.STIRRINGstirred for 1 hour
7. 7
   その他then partitioned between saturated aqueous sodium hydrogencarbonate solution and DCM
8. 8
   乾燥The organic phase was dried over sodium sulfate
9. 9
   ろ過filtered
10. 10
    その他the solvent removed under reduced pressure

実験手順

A solution of trimethylaluminium (2.0 M in hexane, 1 eq) was added slowly to a stirred solution of 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) (1 eq) in dichloromethane (0.1 M) at 0° C. The reaction mixture was stirred for 15 min then a solution of 7-fluoro-2-benzofuran-1(3H)-one (1 eq, Chem. Pharm. Bull., 1985, 33(7), 2809-2820) in DCM was added dropwise. The solution was stirred for 2 h at 0° C. then partitioned between saturated aqueous ammonium chloride solution and ethyl acetate. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The crude 2-fluoro-6-(hydroxymethyl)-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide was dissolved in DCM and to 0° C. To the stirred solution was added dropwise thionyl chloride (1 eq.). The reaction mixture was warmed to room temperature, stirred for 1 hour then partitioned between saturated aqueous sodium hydrogencarbonate solution and DCM. The organic phase was dried over sodium sulfate, filtered and the solvent removed under reduced pressure. The crude 2-(chloromethyl)-6-fluoro-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide thus obtained was dissolved in methanol and cooled to 0° C. To the stirred solution was added sodium methoxide (1.2 eq.) portionwise. The solution was warmed to room temperature and stirred for 18 hours. The solution was concentrated and partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on SPE cartridge (Silica) eluting with DCM-methanol (96:4) affording the title compound (yield 24%).

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