反应详情

温度

25 °C

In a round bottom flask, 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 165 mg, 0.50 mmol) was dissolved in methylene chloride (5 mL) and N,N-dimethylformamide (three drops) at 25° C. under argon. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 270 μL, 0.53 mmol) which produced gas evolution and it was then stirred at 25° C. for 30 minutes after which time it was concentrated in vacuo. The residue was then dissolved in methylene chloride (5 mL) and added dropwise into a solution of 1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-ylamine (prepared in Example 94, 85 mg, 0.50 mmol), 2,6-lutidine (130 μL, 1.00 mmol) and methylene chloride (5 mL) at 0° C. It was then allowed to warm to 25° C. and stirred for 1.5 h. After this time, the reaction was quenched with a small amount of methanol. This was then diluted with ethyl acetate with a very small amount of methanol (<10%) and the organics washed with a saturated 1N aqueous hydrochloric acid solution and a saturated aqueous brine solution it was dried over sodium sulfate, filtered and concentrated with silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40S column, silica gel, 50% ethyl acetate/hexanes) to afford (R)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (211 mg, 90%) as a white foam: [α]31589=−3.04° (c=0.23, methanol); ES-HRMS m/e calcd for C23H32N3O4SCl (M+H)+ 482.1875, observed 482.1873; 1H NMR (300 MHz, DMSO-d6) δ 1.04 (s, 3H, CH3), 1.05 (s, 3H, CH3), 1.11 (m, 2H, CH2), 1.36-1.80 (m, 8H, 4×CH2), 2.09 (m, 1H, CH), 3.13 (s, 3H, OCH3), 3.33 (s, 3H, SO2CH3), 3.92 (m, 1H, ArCHCO), 3.97 (s, 2H, NCH2), 6.45 (d, J=2.2 Hz, 1H, Ar), 7.74 (d, J=2.2 Hz, 1H, Ar), 7.59 (dd, Jm=1.5 Hz, Jo=8.2 Hz, 1H, Ar), 7.70 (d, Jm=1.5 Hz, 1H, Ar), 8.00 (d, Jo=8.2 Hz, 1H, Ar), 10.80 (s, 1H, NH).

1. customat 25° C.
2. customproduced gas evolution and it
3. concentrationwas concentrated in vacuo
4. dissolutionThe residue was then dissolved in methylene chloride (5 mL)
5. temperatureto warm to 25° C.
6. stirringstirred for 1.5 h
7. customAfter this time, the reaction was quenched with a small amount of methanol
8. additionThis was then diluted with ethyl acetate with a very small amount of methanol (<10%)
9. washthe organics washed with a saturated 1N aqueous hydrochloric acid solution
10. dry with materiala saturated aqueous brine solution it was dried over sodium sulfate
11. filtrationfiltered
12. concentrationconcentrated with silica gel (2 g) in vacuo
13. custompurified on Biotage Flash chromatography system (40S column, silica gel, 50% ethyl acetate/hexanes)