2,6-Lutidine → (S)-N-(5-bromo-pyrazin-2-yl)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide

Participants

Reaction Steps

A solution of (S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared as in Example 1, 100 mg, 0.29 mmol) in methylene chloride (4 mL) and N,N-dimethylformamide (4 drops) was treated with a solution of oxalyl chloride in methylene chloride (2.0 M, 150 μL, 0.30 mmol) and stirred for 15 min at room temperature. After this time, the reaction mixture was then concentrated in vacuo and the resulting residue was dissolved in methylene chloride (4 mL) and then added dropwise to a separate reaction flask containing a mixture of 5-bromo-pyrazin-2-ylamine (76 mg, 0.44 mmol) and 2,6-lutidine (100 μL, 0.87 mmol) in methylene chloride (3 mL) at room temperature. The resulting reaction mixture was the stirred room temperature for 1.5 h. The reaction mixture was quenched by the addition of methanol and then diluted with methylene chloride and the organic layer was washed with a 1N aqueous hydrochloric acid solution. The organic layer was then dried, filtered and the filtrate concentrated in vacuo. The crude material was purified via Biotage flash column chromatography (40 S silica gel column, 25% ethyl acetate/hexanes) to afford (S)—N-(5-bromo-pyrazin-2-yl)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide (74 mg, 51%) as a white foam: HR-ES(+) m/e calcd for C21H20N4O2F3Br [M+H]+ 497.0795, observed 497.0796; 1H NMR (400 MHz, DMSO-d6) δ ppm 11.50 (s, 1H), 9.09 (d, J=1.07 Hz, 1H), 8.65 (d, J=1.28 Hz, 1H), 8.02 (dd, J=7.88, 10.44 Hz, 2H), 7.77 (t, J=7.67 Hz, 1H), 5.22 (dd, J=4.90, 10.66 Hz, 1H), 5.04 (d, J=18.33 Hz, 1H), 4.76 (d, J=18.11 Hz, 1H), 1.04-2.19 (m, 11H).

Provenance & Evidence