反应详情

温度

25 °C

In a round bottom flask was placed (R)-2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (75 mg, 0.23 mmol), methylene chloride (2 mL) and N,N-dimethylformamide (3 drops). To this solution was then added a solution of oxalyl chloride in methylene chloride (2.0 M solution, 130 μL, 0.26 mmol). Upon addition there was gas evolution. This was stirred for 30 min at 25° C. after which time it was concentrated in vacuo. The residue was then dissolved in methylene chloride (2 mL) and added dropwise into a solution of 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (prepared in Example 67, 56 mg, 0.23 mmol), 2,6-lutidine (55 μL, 0.46 mmol) and methylene chloride (2 mL) at 0° C. It was then allowed to warm to 25° C. and stirred for 2 h. After this time, the reaction was quenched with a small amount of methanol and then concentrated with silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40S column, silica gel, 40% ethyl acetate/hexanes) to afford (R)—N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (105 mg, 84%) as a white foam: [α]24589=−11.0° (c=0.20, methanol); ES-HRMS m/e calcd for C27H40N4O4SSi (M+H)+ 545.2613, observed 545.2603; 1H NMR (400 MHz, CDCl3) δ −0.05 (s, 6H, 2×SiCH3), 0.84 (s, 9H, 3×CH3), 1.14 (m, 2H, CH2), 1.46-1.94 (m, 8H, 4×CH2), 2.24 (m, 1H, CH), 3.27 (s, 3H, SO2CH3), 3.59 (t, J=7.6 Hz, 1H, ArCH), 3.87 (t, J=5.3 Hz, 2H, OCH2), 4.08 (t, J=5.3 Hz, 2H, NCH2), 6.62 (d, J=2.2 Hz, 1H, Ar), 7.35 (d, J=2.2 Hz, 1H, Ar), 7.84 (dd, Jm=1.8 Hz, Jo=8.3 Hz, 1H, Ar), 7.91 (brs, 1H, NH), 7.97 (d, Jm=1.8 Hz, 1H, Ar), 8.15 (d, Jo=8.3 Hz, 1H, Ar).

1. customIn a round bottom flask was placed
2. additionUpon addition there
3. concentrationwas concentrated in vacuo
4. dissolutionThe residue was then dissolved in methylene chloride (2 mL)
5. temperatureto warm to 25° C.
6. stirringstirred for 2 h
7. customAfter this time, the reaction was quenched with a small amount of methanol
8. concentrationconcentrated with silica gel (2 g) in vacuo
9. custompurified on Biotage Flash chromatography system (40S column, silica gel, 40% ethyl acetate/hexanes)