2,6-Lutidine → (S)-3-cyclopentyl-N-[1-(2-methoxy-2-methyl-propyl)-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 (50 mg, 0.15 mmol, prepared as in Example 1) in methylene chloride (5 mL) and N,N-dimethylformamide (1 drop) cooled to 0° C. was treated with a solution of oxalyl chloride in methylene chloride (2.0 M, 88 μL, 0.18 mmol) and stirred at 0° C. for 10 min. After this time, the reaction mixture was warmed to room temperature and then stirred for another 25 min. After this time, the reaction mixture was then concentrated in vacuo and the residue taken up in methylene chloride (2 mL) and added dropwise to a separate reaction flask containing a mixture of 1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-ylamine (prepared as in US 20080021032, Example 94, 37 mg, 0.22 mmol) and 2,6-lutidine (32 μL, 0.29 mmol) in methylene chloride (5 mL) cooled to 0° C. The resulting reaction mixture was then allowed to warm to room temperature and stirred for 16 h. After such time, the reaction mixture was quenched with a saturated aqueous sodium bicarbonate solution (10 mL) and then extracted with methylene chloride (3×15 mL). The organic layers were then washed with a 1N aqueous hydrochloric acid solution (10 mL), dried over magnesium sulfate, filtered to remove the drying agent, and the filtrate concentrated in vacuo. The crude material was purified via automated flash chromatography (4 g silica gel column, 50% ethyl acetate/hexanes) to afford (S)-3-cyclopentyl-N-[1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide (51 mg, 71%) as a white foam: [α]32D=−41.1°, (c=0.09, methylene chloride); HR-ES(+) m/e calcd for C25H31N4O3F3 [M+H]+ 493.2421, observed 493.2419; 1H NMR (300 MHz, DMSO-d6) δ ppm 10.95 (s, 1H), 8.01 (t, J=8.60 Hz, 2H), 7.68-7.81 (m, 1H), 7.49 (d, J=1.81 Hz, 1H), 6.44 (d, J=2.11 Hz, 1H), 4.97-5.17 (m, 2H), 4.71 (d, J=18.41 Hz, 1H), 3.92-4.08 (m, 2H), 3.06-3.22 (m, 3H), 0.93-2.16 (m, 17H).

1. temperatureAfter this time, the reaction mixture was warmed to room temperature
2. stirringstirred for another 25 min
3. concentrationAfter this time, the reaction mixture was then concentrated in vacuo
4. additionadded dropwise to a separate reaction flask
5. additioncontaining
6. temperaturecooled to 0° C
7. customThe resulting reaction mixture
8. temperatureto warm to room temperature
9. stirringstirred for 16 h
10. customAfter such time, the reaction mixture was quenched with a saturated aqueous sodium bicarbonate solution (10 mL)
11. extractionextracted with methylene chloride (3×15 mL)
12. washThe organic layers were then washed with a 1N aqueous hydrochloric acid solution (10 mL)
13. dry with materialdried over magnesium sulfate
14. filtrationfiltered
15. customto remove the drying agent
16. concentrationthe filtrate concentrated in vacuo
17. customThe crude material was purified

ORD record

ord-4aec54dfa15d45a9b3ae7cf3baa4f747

Source dataset

uspto-grants-2014_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08697705B2