2-oxaspiro[4.4]nonane-1,3-dione → 1-({5-(Quinolin-2-ylmethoxy)-1-[4-(trifluoromethyl)benzyl]-1H-benzimidazol-2-yl}methyl)cyclopentanecarboxylic acid

Temperature

80 °C

To a 10 mL round bottomed flask, equipped with a reflux condenser, were added 4-(quinolin-2-ylmethoxy)-N1-(4-(trifluoromethyl)benzyl)benzene-1,2-diamine (53 mg, 0.12 mmol), 2-oxaspiro[4.4]nonane-1,3-dione (19 mg, 0.12 mmol) and acetonitrile (1.3 mL). The flask was heated to 80° C. for 72 hours. The mixture was concentrated and the residue was dissolved in ethanol (2 mL) followed by the slow addition of HCl (0.6 mL, 12 N). The mixture was then heated to 80° C. until the starting material had been consumed. The reaction mixture was cooled to RT, concentrated to dryness and the resulting residue was dissolved in THF (3.4 mL) and methanol (3.4 mL). To this solution was added LiOH (3.6 mL, 1 M aq.) and the reaction was monitored by LCMS until the ester was consumed. The reaction mixture was then partitioned between 1 mL of aqueous NH4Cl and EtOAc. The aqueous layer was further extracted with EtOAc (3×20 mL). The combined organics were dried over sodium sulfate, filtered and concentrated to dryness. The crude residue was purified using reverse phase HPLC to provide the title compound. MS (ESI): mass calcd. for C32H28F3N3O3, 559.21; m/z found, 5602 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.13 (d, J=8.4 Hz, 1H), 8.07 (d, J=8.5 Hz, 1H), 7.79 (d, J=8.2 Hz, 1H), 7.71 (t, J=7.7 Hz, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.58-7.44 (m, 3H), 7.35 (s, 1H), 7.14-6.85 (m, 4H), 5.32 (s, 4H), 3.04 (s, 2H), 2.43-2.14 (m, 2H), 1.75-1.31 (m, 7H).

1. customTo a 10 mL round bottomed flask, equipped with a reflux condenser
2. concentrationThe mixture was concentrated
3. dissolutionthe residue was dissolved in ethanol (2 mL)
4. additionfollowed by the slow addition of HCl (0.6 mL, 12 N)
5. temperatureThe mixture was then heated to 80° C. until the starting material
6. customhad been consumed
7. temperatureThe reaction mixture was cooled to RT
8. concentrationconcentrated to dryness
9. dissolutionthe resulting residue was dissolved in THF (3.4 mL)
10. additionTo this solution was added LiOH (3.6 mL, 1 M aq.)
11. customwas consumed
12. customThe reaction mixture was then partitioned between 1 mL of aqueous NH4Cl and EtOAc
13. extractionThe aqueous layer was further extracted with EtOAc (3×20 mL)
14. dry with materialThe combined organics were dried over sodium sulfate
15. filtrationfiltered
16. concentrationconcentrated to dryness
17. customThe crude residue was purified

ORD record

ord-bc85df6aad64472badafbf08e163280a

Source dataset

uspto-grants-2015_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09067917B2