Reaction Steps
To a solution of 7-(5-cyclopropylpyrazin-2-yloxy)hexahydro-pyrrolo[1,2-a]pyrazin-1(2H)-one (50 mg, 0.182 mmol) from Step 3 [3:1 (7R,8aS: 7R,8aR) diastereomer ratio] in N,N-dimethylformamide (0.7 mL) under nitrogen was added sodium hydride (60% weight suspension in mineral oil; 8.75 mg, 0.219 mmol), and the resulting suspension was stirred at room temperature. After 20 minutes, the suspension was treated with 1-(bromomethyl)-3-(trifluoromethyl)benzene (0.033 mL, 0.219 mmol) with stirring continued for 4 hours at room temperature. The reaction mixture was partitioned between water (3 mL) and ethyl acetate (3×2 mL), and the organic phase was dried over sodium sulfate. The solvent was concentrated under a stream of nitrogen, and the crude material was purified by flash chromatography on a 12 g silica gel cartridge eluted with a gradient 0-5% methanol/dichloromethane over 17 minutes to give the crude product as an oil. The crude oil (40 mg) was loaded onto a 2×0.25 mm silica gel prep plate and eluted with ethyl acetate to give the title compound (21 mg, 0.049 mmol, 26.6% yield) as the first of 2 diastereomers to elute as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 8.07 (d, J=1.0 Hz, 1H), 7.94 (d, J=1.1 Hz, 1H), 7.55 (dd, J=4.4, 3.4 Hz, 1H), 7.48 (t, J=9.0 Hz, 3H), 5.44 (dd, J=6.9, 5.7 Hz, 1H), 4.73 (d, J=14.8 Hz, 1H), 4.58 (d, J=14.8 Hz, 1H), 3.71 (t, J=8.0 Hz, 1H), 3.46 (dt, J=12.2, 7.1 Hz, 1H), 3.38 (dd, J=10.9, 5.7 Hz, 1H), 3.20 (dt, J=12.1, 3.9 Hz, 1H), 3.02 (dd, J=6.7, 3.8 Hz, 2H), 2.88 (dd, J=10.8, 2.9 Hz, 1H), 2.53 (dt, J=15.2, 7.6 Hz, 1H), 2.44 (dd, J=14.5, 7.8 Hz, 1H), 2.03-1.95 (m, 1H), 1.00-0.88 (m, 4H); MS (ESI+) m/z 433 (M+H)+.
