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

Participants

Reaction Conditions

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, 125 mg, 0.37 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, 220 μL, 0.44 mmol) and stirred for 10 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 it was added to a flask containing 5-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-pyrazin-2-ylamine (prepared as in WO2004052869, Example 54, 107 mg, 0.55 mmol) and 2,6-lutidine (81 μL, 0.73 mmol) in methylene chloride (10 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 (10 mL), 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 (12 g silica gel column, 15-40% ethyl acetate/hexanes) to afford (S)-3-cyclopentyl-N-[5-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-pyrazin-2-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide (78 mg, 41%) as a white foam: [α]27D=−18.0° (c=0.15, methylene chloride); HR-ES(+) m/e calcd for C26H29N4O4F3 [M+Na]+ 541.2033, observed 541.2030; 1H NMR (300 MHz, DMSO-d6) δ 11.37 (s, 1H), 9.21 (d, J=1.21 Hz, 1H), 8.48 (d, J=1.21 Hz, 1H), 8.02 (t, J=8.00 Hz, 2H), 7.72-7.82 (m, 1H), 5.12-5.29 (m, 2H), 5.05 (d, J=17.81 Hz, 1H), 4.76 (d, J=18.11 Hz, 1H), 4.35 (dd, J=6.64, 8.45 Hz, 1H), 3.93 (dd, J=6.64, 8.45 Hz, 1H), 1.04-2.20 (m, 17H).

Provenance & Evidence