反应详情

To a mixture of acetonitrile (500 μL, 10.0 mmol) in THF (30 mL) at RT was added a solution of potassium 2-methylbutan-2-olate in THF (1.7 M, 16.9 mL, 28.7 mmol), followed by methyl 1-methylcyclohexanecarboxylate (2.24 g, 14.4 mmol) and the reaction mixture maintained at RT for 17 hr and then concentrated to ˜20 mL in vacuo. The residue was diluted with EtOH (20 mL), treated with p-tolylhydrazine hydrochloride (1.52 g, 9.57 mmol) and the resulting mixture acidified to pH1 by the addition of conc hydrochloric acid and then heated to 70° C. for 5 hr. The mixture was cooled to RT for 16 hr and concentrated to ˜20 mL in vacuo, diluted with water (30 mL) and was then basified to pH 12 by the addition of 2M aq NaOH. The resulting solution was extracted with EtOAc (2×20 mL) and the combined organic extracts were washed with brine (30 mL) and then dried and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, EtOAc in isohexane, 0-20%, gradient elution) to afford the title compound, Intermediate A33, as a yellow oil, (˜50% purity, containing 3-(1-methylcyclohexyl)-3-oxopropanenitrile) (1.30 g, 25%); Rt 1.97 min (Method 2); m/z 270 (M+H)+ (ES+). The material was used in subsequent reactions without further purification.

1. concentrationconcentrated to ˜20 mL in vacuo
2. additionThe residue was diluted with EtOH (20 mL)
3. temperatureheated to 70° C. for 5 hr
4. temperatureThe mixture was cooled to RT for 16 hr
5. concentrationconcentrated to ˜20 mL in vacuo
6. additiondiluted with water (30 mL)
7. additionwas then basified to pH 12 by the addition of 2M aq NaOH
8. extractionThe resulting solution was extracted with EtOAc (2×20 mL)
9. washthe combined organic extracts were washed with brine (30 mL)
10. customdried
11. customevaporated in vacuo
12. customThe residue was purified by flash column chromatography (SiO2, EtOAc in isohexane, 0-20%, gradient elution)