甲基 1-甲基环己烷-1-羧酸乙酯

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 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. concentrated to ˜20 mL in vacuo The residue was diluted with EtOH (20 mL) heated to 70° C. for 5 hr The mixture was cooled to RT for 16 hr concentrated to ˜20 mL in vacuo diluted with water (30 mL) was then basified to pH 12 by the addition of 2M aq NaOH The resulting solution was extracted with EtOAc (2×20 mL) the combined organic extracts were washed with brine (30 mL) dried evaporated in vacuo The residue was purified by flash column chromatography (SiO2, EtOAc in isohexane, 0-20%, gradient elution)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 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. concentrated to ˜20 mL in vacuo The residue was diluted with EtOH (20 mL) heated to 70° C. for 5 hr The mixture was cooled to RT for 16 hr concentrated to ˜20 mL in vacuo diluted with water (30 mL) was then basified to pH 12 by the addition of 2M aq NaOH The resulting solution was extracted with EtOAc (2×20 mL) the combined organic extracts were washed with brine (30 mL) dried evaporated in vacuo The residue was purified by flash column chromatography (SiO2, EtOAc in isohexane, 0-20%, gradient elution)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Treat a solution of 1-methylcyclohexane carboxylic acid (7.11 g, 50.0 mmol) in MeOH (10 mL) and Et2O (40 mL) dropwise with trimethylsilyldiazomethane (2.0 M/hexanes; 26 mL, 52 mmol). Stir the reaction mixture at room temperature overnight, then concentrate under reduced pressure to yield the title compound as a clear, pale yellow oil (7.811 g, 50 mmol; 100%). MS(ES): m/z=156 [M+H]. concentrate under reduced pressure

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Sodium hydrogen carbonate (1.68 g, 20.0 mmol) was added to a solution of trans-4-aminomethyl cyclohexanecarboxylic acid methyl ester hydrochloride (2.07 g, 10.0 mmol) obtained in Step 1, 9-fluorenylmethoxycarbonyl isothiocyanate (2.81 g, 10.0 mmol) in chloroform (40 ml) while ice-cooled. The reaction solution was stirred at room temperature for 16 hours, piperidine (5 ml, 50 mmol) was added, and the mixture was stirred at room temperature for further 6 hours. Trans-4-thiouredide methylcyclohexane carboxylic acid methyl ester (1.55 g, 67%) was obtained by concentrating the reaction solution in vacuo and purifying the obtained solid by silica gel column chromatography (ethyl acetate). cooled the mixture was stirred at room temperature for further 6 hours

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 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. concentrated to ˜20 mL in vacuo The residue was diluted with EtOH (20 mL) heated to 70° C. for 5 hr The mixture was cooled to RT for 16 hr concentrated to ˜20 mL in vacuo diluted with water (30 mL) was then basified to pH 12 by the addition of 2M aq NaOH The resulting solution was extracted with EtOAc (2×20 mL) the combined organic extracts were washed with brine (30 mL) dried evaporated in vacuo The residue was purified by flash column chromatography (SiO2, EtOAc in isohexane, 0-20%, gradient elution)