Potassium Carbonate → Gsk-2879552

Participants

Reaction Conditions

Reaction Steps

To the solution of 2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (200 mg, 0.613 mmol, Example 11b) and 4-(bromomethyl)benzoic acid (198 mg, 0.919 mmol) in acetonitrile (6 mL) was added potassium carbonate (254 mg, 1.838 mmol). The reaction mixture was stirred for 3 hours at the 90° C. The reaction mixture was then filtered and evaporated. The crude oil was mixed with 10 mL of 10% acetic acid and 10 mL of ethyl acetate. Layers were separated, and the organic layer was discharged. Aqueous layer was neutralized with 1 M Na2CO3, and the product was extracted into 10 mL of ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered and evaporated. The oil was dissolved in 6 ml of EtOH and 3 ml of 1 M NaOH. The reaction mixture was stirred for 20 min, and then it was concentrated. The solution was then partioned between 2 ml of water and 5 mL of ethyl acetate. The organic layer was separated and evaporated. The oil was purified on preparatory HPLC (2 to 10% AcCN: H2O with 0.1% formic acid modifier). The fractions were collected. To each fraction was added 1 ml of 1 M HCl, and the fractions were evaporated to dryness. 4-((4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic acid (50 mg, 0.118 mmol, 19.33% yield) was isolated as a white solid. 1H NMR (400 MHz, METHANOL-d4) δ 8.16 (d, J=8.34 Hz, 2H), 7.70 (d, J=8.34 Hz, 2H), 7.30-7.37 (m, 2H), 7.23-7.29 (m, 1H), 7.20 (d, J=7.33 Hz, 2H), 4.44 (br. s., 2H), 3.57 (d, J=11.62 Hz, 2H), 3.07-3.27 (m, 4H), 3.04 (dt, J=3.95, 7.52 Hz, 1H), 2.59 (ddd, J=3.54, 6.57, 10.11 Hz, 1H), 2.12 (d, J=13.89 Hz, 3H), 1.54-1.81 (m, 3H), 1.42 (q, 1H); LC-MS Rt=0.47 min; MS (ESI): 365.3 [M+H]+.

Provenance & Evidence