4-Fluorobenzoic Acid → 4-fluoro-N-{(3aR,4S,6aS)-2-[6-(trifluoromethyl)pyridin-2-yl]octahydrocyclopenta[c]pyrrol-4-yl}benzamide

p-Fluorobenzoic acid (56.8 mg, 0.405 mmol), 1-hydroxybenzotriazole hydrate (62.1 mg, 0.405 mmol 1), and (3aR,4S,6aS)-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine from Example 264 Step A (100 mg, 0.369 mmol) were combined in dichloromethane (1.2 mL) to give a colorless solution. After 20 minutes, N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.072 mL, 0.405 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with water and extracted with 2×2 mL of dichloromethane. The combined extracts were applied directly to a 12 g silica gel cartridge and purified with a gradient of 1-10% methanol in (2 N ammonia)/dichloromethane over 20 minutes to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.90 (d, J=6.9, 1H), 8.29-8.19 (m, 2H), 7.56-7.47 (m, 1H), 7.17 (ddd, J=9.7, 5.9, 2.5, 2H), 6.99 (d, J=7.2, 1H), 6.53 (d, J=8.6, 1H), 4.64-4.52 (m, 1H), 3.80 (dd, J=11.0, 3.7, 1H), 3.63 (dd, J=10.9, 8.2, 1H), 3.51 (dd, J=10.8, 8.4, 1H), 3.30 (dd, J=10.9, 4.6, 1H), 2.90-2.77 (m, 1H), 2.77-2.64 (m, 1H), 2.23 (ddd, J=19.5, 7.1, 4.7, 1H), 1.93 (dtd, J=12.7, 8.0, 4.6, 1H), 1.81 (ddd, J=16.4, 12.7, 8.1, 1H), 1.40 (dt, J=13.2, 7.6, 1H); MS (ESI+) m/z 394 (M+H)+.

1. customto give a colorless solution
2. customThe reaction mixture was quenched with water
3. extractionextracted with 2×2 mL of dichloromethane
4. custompurified with a gradient of 1-10% methanol in (2 N ammonia)/dichloromethane over 20 minutes

ORD record

ord-7d745b5411dc435cb0cdf3fa72ba7952

Source dataset

uspto-grants-2014_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08691865B2