Potassium Carbonate → Gsk-2879552

Temperature

90 °C

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]+.

1. filtrationThe reaction mixture was then filtered
2. customevaporated
3. additionThe crude oil was mixed with 10 mL of 10% acetic acid and 10 mL of ethyl acetate
4. customLayers were separated
5. extractionthe product was extracted into 10 mL of ethyl acetate
6. washThe organic layer was washed with brine
7. dry with materialdried over MgSO4
8. filtrationfiltered
9. customevaporated
10. dissolutionThe oil was dissolved in 6 ml of EtOH
11. stirringThe reaction mixture was stirred for 20 min
12. concentrationit was concentrated
13. customThe organic layer was separated
14. customevaporated
15. customThe oil was purified on preparatory HPLC (2 to 10% AcCN: H2O with 0.1% formic acid modifier)
16. customThe fractions were collected
17. additionTo each fraction was added 1 ml of 1 M HCl
18. customthe fractions were evaporated to dryness

ORD record

ord-f381a42de1464927bdee5c1b4bf9a851

Source dataset

uspto-grants-2016_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09346840B2