2,6-Lutidine → (S)-3-cyclopentyl-N-[1-(2-isopropoy-ethyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide

Temperature

0 °C

A solution of (S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared as in Example 1, 160 mg, 0.47 mmol) in methylene chloride (10 mL) was treated with N,N-dimethylformamide (1 drop) and cooled to 0° C. It was then treated with a solution of oxalyl chloride (2.0 M in methylene chloride, 281 μL, 0.56 mmol) and stirred for 15 min at 0° C. and then warmed to room temperature and stirred for 30 min. After this time, the reaction mixture was concentrated in vacuo to about 1 mL and then methylene chloride was added (3 mL). Half of the resulting volume (˜2 mL, ˜0.235 mmol of the in situ generated acid chloride) was added to a flask containing 1-(2-isopropoxy-ethyl)-1H-pyrazol-3-ylamine (prepared as in US20080021032, Example 101, 60 mg, 0.35 mmol) and 2,6-lutidine (52 μL, 0.47 mmol) in methylene chloride (5 mL) at 0° C. The reaction mixture was then allowed to warm up to room temperature and stirred overnight for 16 h. After this time, the reaction mixture was quenched with an aqueous saturated sodium bicarbonate solution (10 mL) and extracted with methylene chloride (3×10 mL). The organic layers were then combined and washed with a 1N aqueous hydrochloric acid solution, dried over magnesium sulfate, filtered to remove the drying agent and the filtrate concentrated in vacuo. The crude material was purified using an Analogix Intelliflash 280 chromatography system (4 g silica gel column, 45-55% ethyl acetate/hexanes) to afford (S)-3-cyclopentyl-N-[1-(2-isopropoy-ethyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide (89 mg, 77%) as a white foam: HR-ES(+) m/e calcd for C25H31N4O3F3 [M+H]+ 493.2421, observed 493.2422; 1H NMR (300 MHz, DMSO-d6) δ 10.93 (s, 1H), 7.89-8.19 (m, 2H), 7.68-7.83 (m, 1H), 7.56 (d, J=2.11 Hz, 1H), 6.40 (d, J=2.11 Hz, 1H), 4.91-5.25 (m, 2H), 4.71 (d, J=18.41 Hz, 1H), 4.10 (t, J=5.28 Hz, 2H), 3.57-3.79 (m, 2H), 3.47 (td, J=6.15, 12.15 Hz, 1H), 0.89-2.17 (m, 17H).

1. temperaturewarmed to room temperature
2. stirringstirred for 30 min
3. concentrationAfter this time, the reaction mixture was concentrated in vacuo to about 1 mL
4. additionmethylene chloride was added (3 mL)
5. additionwas added to a flask
6. temperatureto warm up to room temperature
7. stirringstirred overnight for 16 h
8. customAfter this time, the reaction mixture was quenched with an aqueous saturated sodium bicarbonate solution (10 mL)
9. extractionextracted with methylene chloride (3×10 mL)
10. washwashed with a 1N aqueous hydrochloric acid solution
11. dry with materialdried over magnesium sulfate
12. filtrationfiltered
13. customto remove the drying agent
14. concentrationthe filtrate concentrated in vacuo
15. customThe crude material was purified

ORD record

ord-72cd897446864ea996dd93a046bad9b9

Source dataset

uspto-grants-2014_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08697705B2