2,6-Lutidine → N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-3-cyclopentyl-2(R)-(3-trifluoromethyl-phenyl)-propionamide

Temperature

25 °C

3-cyclopentyl-2(R)-(3-trifluoromethyl-phenyl)-propionic acid (92 mg, 0.32 mmol) was dissolved in methylene chloride (2 mL) and N,N-dimethylfomamide (three drops) at 25° C. under argon. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 190 μL, 0.35 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 (80 μL, 0.64 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, 78 mg, 0.32 mmol) in methylene chloride (1 mL) and the reaction was allowed to warm up to 25° C. and stirred for 2 h. After this time the reaction quenched with a small amount of methanol and then diluted with methylene chloride. The reaction was then transferred to a separatory funnel and washed with 1 N aqueous hydrochloric acid solution (1×10 mL) and then a saturated brine solution (1×10 mL). The organic layer was then dried over sodium sulfate and concentrated with silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40M column, silica gel, 40% ethyl acetate/hexanes) (40S column, Silica gel, 20% ethyl acetate/hexanes) to afford N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-3-cyclopentyl-2(R)-(3-trifluoromethyl-phenyl)-propionamide as a colorless gum: [α]25589=−14.5° (c=0.22, methanol); ES-HRMS m/e calcd for C26H38N3O2SiF3 (M+H)+ 510.2758, observed 510.2749; 1H NMR (400 MHz, DMSO-d6) δ ppm −0.09 (s, 6H, 2×SiCH3), 0.77 (s, 9H, 3×CH3), 1.06-1.18 (m, 2H, CH2), 1.37-1.79 (m, 8H, 4×CH2), 2.08-2.18 (m, 1H, CH), 3.84 (t, J=5.1 Hz, 2H, OCH2), 3.90 (dd, J=9.4, 5.3 Hz, 1H, ArCH), 4.04 (t, J=5.1 Hz, 2H, NCH2), 6.41 (d, J=2.3 Hz, 1H, Ar), 7.51 (d, J=2.3 Hz, 1H, Ar), 7.54-7.72 (m, 4H, Ar), 10.72 (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 2 h
7. customAfter this time the reaction quenched with a small amount of methanol
8. additiondiluted with methylene chloride
9. customThe reaction was then transferred to a separatory funnel
10. washwashed with 1 N aqueous hydrochloric acid solution (1×10 mL)
11. dry with materialThe organic layer was then dried over sodium sulfate
12. concentrationconcentrated with silica gel (2 g) in vacuo
13. custompurified on Biotage Flash chromatography system (40M column, silica gel, 40% ethyl acetate/hexanes) (40S column, Silica gel, 20% ethyl acetate/hexanes)

ORD record

ord-25b6843a455c47a594c44df1abd1877f

Source dataset

uspto-grants-2011_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07935699B2