Ureas derivative and application thereof in preventing and treating inflammation

[0026] Example 1: Synthesis of 1-hydroxyl-1-(2-(3-nitrophenyl)-2,3-dihydro-1H-inden-1-yl)urea

[0027] Synthesis of 1-1,2-bromo-2,3-dihydro-1H-inden-1-ylmethanesulfonic acid:

[0028]

[0029] To a solution of 2-bromo-2,3-dihydro-1H-inden-1-ol (10.0 g, 46.93 mmol), triethylamine (10.8 g, 106.73 mmol) in DCM (50 mL) at 0 °C was added dropwise Methanesulfonyl chloride MsCl (9.9 g, 86.43 mmol) was added dropwise over 30 minutes. The mixture was stirred for an additional 2 hours, then allowed to warm to room temperature. Water (50 mL) was added, the DCM layer was separated and the aqueous phase was extracted twice more with DCM (2 x 30 mL). The combined organic phases were washed with brine (50 mL), then washed with Na 2 SO 4 dry. The solvent was removed under vacuum to give 2-bromo-2,3-dihydro-1H-inden-1-ylmethanesulfonic acid as a light oil, yield 13.53 g, 99% yield, which was directly obtained without further purification for the next step. 1 H-NMR (400MHz, CDCl3) δ: 3.1

[0039] Example 2: Synthesis of 1-hydroxyl-1-(2-(3-fluoro-phenyl)-2,3-dihydro-1H-inden-1-yl)urea:

[0040]

[0041] 1-(2-Bromo-2,3-dihydro-1H-inden-1-yl)-1-hydroxyurea (10.77 g, 39.73 mmol) was dissolved in 96 mL of H 2 O:EtOH (1:1) mixture and placed in a three-necked flask (250mL). 3-Fluoro-phenylboronic acid (55.47 mmol) and potassium carbonate (8.29 g, 59.99 mmol) were added to the mixture. Then PdNPs catalyst (0.4 mmol% Pd) was added, and the mixture was vigorously stirred at 60 °C for 10 min under nitrogen atmosphere. The reaction mixture was added to 0.2 mol / L sodium hydroxide solution (55 mL) and extracted with ethyl acetate (40 mL). The organic layers were combined and crystallized by volatilization in air to give the solid product 1-hydroxy-1-(2-(3-fluoro-phenyl)-2,3-dihydro-1H-inden-1-yl)urea, 10.45 g, the yield was 92%. LC-MS (ESI, pos, ion) m / z: 287 [M+H].

[0042] Example 3: Synthesis of 1-hydroxyl-1-(2-phenyl-2,3-dihydro-1H-inden-1-yl)urea:

[0043]

[0044] 1-(2-Bromo-2,3-dihydro-1H-inden-1-yl)-1-hydroxyurea (10.77 g, 39.73 mmol) was dissolved in 96 mL of H 2 O:EtOH (1:1) mixture and placed in a three-necked flask (250mL). Phenylboronic acid (55.47 mmol) and potassium carbonate (8.29 g, 59.99 mmol) were added to the mixture. Then PdNPs catalyst (0.4 mmol% Pd) was added, and the mixture was vigorously stirred at 60 °C for 10 min under nitrogen atmosphere. The reaction mixture was added to 0.2 mol / L sodium hydroxide solution (55 mL) and extracted with ethyl acetate (40 mL). The organic layers were combined and crystallized by volatilization in air to obtain the solid product 1-hydroxyl-1-(2-phenyl-2,3-dihydro-1H-inden-1-yl)urea, 9.05g, with a yield of 85 %. LC-MS (ESI, pos, ion) m / z: 269 [M+H].