反应详情

To a solution of 1-[1,1-dimethylethoxycarbonyl]-4-[3-(1,1-dimethylpropylamino)-2-pyridinyl]piperazine (PREPARATION 66, 4.99 g) in methylene chloride (75 ml) under nitrogen at 0° is added trifluoroacetic acid (14.3 ml) over 1 min. The resulting mixture is warmed to 20°-25°, stirred for 15 hrs, and then added to a solution of sodium hydroxide (7.44 g) in water (175 ml) at 0°. The layers are separated, the aqueous phase is extracted with methylene chloride (3×70ml), and the combined organic layer is washed with saline (60 ml), dried over sodium sulfate, and concentrated under reduced pressure to give the unprotected intermediate (Rf =0.14, TLC, methanol/chloroform, 10/90). In a flame-dried flask under nitrogen, 5-nitroindole-2-carboxylic acid (2.13 g) and 1,1'-carbonyldiimidazole (1.75 g) are dissolved in dry tetrahydrofuran and stirred for 3 hrs at 20°-25°. Then a solution of the intermediate (2.57 g) in dry tetrahydrofuran (3ml) is added and the resulting mixture is stirred for 1.8 days. The reaction mixture is filtered to give the title compound, NMR (dimethylsulfoxide-de) 12.41, 8.65, 8.09, 7.58, 7.16, 7.11, 6.91, 4.57, 3.93, 3.00, 1.71, 1.31 and 0.84. The filtrate is concentrated and is triturated with cold methanol to give an additional mount of the title compound.

1. temperatureThe resulting mixture is warmed to 20°-25°
2. customThe layers are separated
3. extractionthe aqueous phase is extracted with methylene chloride (3×70ml)
4. washthe combined organic layer is washed with saline (60 ml)
5. dry with materialdried over sodium sulfate
6. concentrationconcentrated under reduced pressure
7. customto give the unprotected intermediate (Rf =0.14, TLC, methanol/chloroform, 10/90)
8. stirringstirred for 3 hrs at 20°-25°
9. stirringthe resulting mixture is stirred for 1.8 days
10. filtrationThe reaction mixture is filtered