反应详情

温度

25 °C

A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(tetrahydro-pyran-4-yl)-propionic acid (prepared as in PCT WO 2003/095438 A1, Example 20, 144 mg, 0.41 mmol) was dissolved in methylene chloride (4 mL) and N,N-dimethylfomamide (three drops) at 25° C. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 0.21 mL, 0.43 mmol) which produced gas evolution and it was then stirred at 25° C. for 30 minutes. After this time, the reaction was cooled to 0° C. and 2,6-lutidine (100 μL, 0.83 mmol) was added to the flask and it was stirred for 15 min. To this was then added a solution of 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (prepared in Example 67, 100 mg, 0.41 mmol) in methylene chloride (2 mL) and the reaction was allowed to warm up to 25° C. and stirred for 1 h. After this time the reaction was diluted with a small amount of methanol in methylene chloride and washed with aqueous 1 N hydrochloric acid solution and then a saturated aqueous brine solution/water reaction (1/1). Flash chromatography using Biotage system (40S column, Silica gel, 50% ethyl acetate/hexanes) afforded N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-2-(3-chloro-4-methanesulfonyl-phenyl)-3-(tetrahydro-pyran-4-yl)-propionamide (158 mg, 67%) as an off-white foam: ES-HRMS m/e calcd for C26H40N3O5SSiCl (M+H)+ 570.2219, observed 570.2210; 1H NMR (400 MHz, DMSO-d6) δ ppm −0.08 (s, 6H, 2×SiCH3), 0.78 (s, 9H, 3×CH3), 1.13-1.27 (m, 2H, CH2), 1.29-1.43 (m, 1H, CH of CH2), 1.50-1.71 (m, 3H, CH of CH2 and CH2), 2.01-2.12 (m, 1H, CH), 3.20 (m, 2H, OCH2), 3.34 (s, 3H, SO2CH3), 3.76-3.88 (m, 4 H, OCH2 and SiOCH2), 3.97-4.10 (m, 3H, CH and NCH2), 6.42 (d, J=2.3 Hz, 1H, Ar), 7.53 (d, J=2.3 Hz, 1H, Ar), 7.60 (dd, Jo=8.2 Hz, Jm=1.6 Hz, 1H, Ar), 7.71 (d, Jm=1.6 Hz, 1H, Ar), 8.01 (d, Jo=8.2 Hz, 1H, Ar), 10.81 (s, 1H, NH).

1. customat 25° C
2. customproduced gas evolution and it
3. temperatureAfter this time, the reaction was cooled to 0° C.
4. stirringwas stirred for 15 min
5. temperatureto warm up to 25° C.
6. stirringstirred for 1 h
7. washwashed with aqueous 1 N hydrochloric acid solution
8. customa saturated aqueous brine solution/water reaction (1/1)