反应详情

温度

135 °C

A mixture of (R)-3-(4-bromophenyl)-1-(2-methylpyridin-4-yl)-3-o-tolylpropan-1-one (example 142, step 2; 3.5 g, 8.88 mmol), diethyl malonate (67.5 g, 421 mmol) sodium hydride (724 mg, 18.1 mmol), tris(dibenzylideneacetone)dipalladium(0) (475 mg, 518 μmol) and 2-(di-tert-butylphosphino)biphenyl (155 mg, 518 μmol) in was heated at 135° C. for 90 min. After cooling the reaction mixture was partitioned between sat. aq. ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was dissolved in water (13 mL) and acetic acid (19 mL, 19.8 mmol) then under cooling conc. sulfuric acid (11.9 g, 116 mmol) was added dropwise at a temperature below 30° C. The reaction mixture was heated at 120° C. for 16 h, then partitioned between 2 M aq. sodium hydroxide solution and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in tetrahydrofuran (110 mL), then after addition of 1 M aq. lithium hydroxide solution (350 mL, 350 mmol) and methanol (110 mL) the reaction mixture was stirred for 3 h at room temperature. After addition of 1 M aq. potassium hydrogensulfate solution (60 mL) and sat. aq. ammonium chloride solution (100 mL) the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. Chromatography (SiO2) produced the title compound (1.96 g, 59%). White foam, MS (ESI+): m/z=374.3 ([M+H]+).

1. temperatureAfter cooling the reaction mixture
2. customwas partitioned between sat. aq. ammonium chloride solution and ethyl acetate
3. washThe organic layer was washed with brine
4. dry with materialdried over magnesium sulfate
5. filtrationfiltered
6. concentrationconcentrated
7. dissolutionThe residue was dissolved in water (13 mL)
8. temperatureThe reaction mixture was heated at 120° C. for 16 h
9. custompartitioned between 2 M aq. sodium hydroxide solution and ethyl acetate
10. washThe organic layer was washed with brine
11. dry with materialdried over sodium sulfate
12. filtrationfiltered
13. concentrationconcentrated in vacuo
14. dissolutionThe residue was dissolved in tetrahydrofuran (110 mL)
15. extractionwas extracted with ethyl acetate
16. washThe organic layer was washed with brine
17. dry with materialdried over sodium sulfate
18. filtrationfiltered
19. concentrationconcentrated