反应详情

温度

35 °C

To a stirred and chilled (ice/water bath) solution of crude 5-(3,5-dicyano-2,6-dimethyl-1,4-dihydro-pyridin-4-yl)-3-(2-hydroxy-ethylamino)-indazole-1-carboxylic acid tert-butyl ester (1 g) in THF (157 mL), under argon, was added sequentially 4-methylmorpholine (5.2 mL) and mesyl chloride (MsCl, CH3SO2Cl, 0.89 mL) dropwise. The mixture was allowed to warm to room temperature overnight before morpholine (41 mL) was added. Stirring was continued overnight before heating to 35° C. On cooling, triethylamine was added, the mixture concentrated to ca. one third the volume and the residue cooled (ice/water bath). The mixture was quenched with ice and aqueous sodium carbonate solution and the extracted with EtOAc. The combined organic extracts were dried and concentrated. The residue was taken up in THF (15 mL), HCl (15 mL) was added and the mixture was heated for 1.5 h at 60° C. (bath temperature). On cooling, the mixture was poured carefully onto aqueous sodium hydrogencarbonate solution and extracted with EtOAc. The combined organic extracts were dried and concentrated. The residue was purified by preparative reverse phase HPLC to give 1,4-dihydro-2,6-dimethyl-4-[3-[[2-(4-morpholinyl)ethyl]amino]-1H-indazol-5-yl]-3,5-pyridinedicarbonitrile (60 mg) (Cpd. No. 307, Table 8). 1H-NMR (DMSO-D6, 300 MHz): δ=11.46 (br s, 1H), 9.50 (br s, 1H), 7.56 (s, 1H), 7.25 (d, 1H), 7.17 (dd, 1H), 5.93 (t, 1H), 4.40 (s, 1H), 3.60 (m, 4H), 3.40 (partially obscured by solvent, 2H), 2.59 (t, 2H), 2.44 (m, 4H), 2.05 (s, 6H) ppm.

1. additionwas added
2. stirringStirring
3. temperatureOn cooling
4. concentrationthe mixture concentrated
5. temperaturethe residue cooled (ice/water bath)
6. customThe mixture was quenched with ice and aqueous sodium carbonate solution
7. extractionthe extracted with EtOAc
8. customThe combined organic extracts were dried
9. concentrationconcentrated
10. additionHCl (15 mL) was added
11. temperaturethe mixture was heated for 1.5 h at 60° C. (bath temperature)
12. temperatureOn cooling
13. additionthe mixture was poured carefully onto aqueous sodium hydrogencarbonate solution
14. extractionextracted with EtOAc
15. customThe combined organic extracts were dried
16. concentrationconcentrated
17. customThe residue was purified by preparative reverse phase HPLC