Sodium Carbonate → 7-(4-Cyclopropyl-5-fluoropyridin-3-yl)-9-fluoro-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline

HRID 921972Notes

Reaction equation

HRID 921972 reaction equation
Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:11])[C:7]=1[CH:8]1[CH2:10][CH2:9]1.C(=O)([O-])[O-].[Na+].[Na+].[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]2[C:28]=1[N:27]1[C:29]([CH3:32])=[N:30][N:31]=[C:26]1[CH2:25][CH2:24]2>COCCOC.O>[CH:8]1([C:7]2[C:6]([F:11])=[CH:5][N:4]=[CH:3][C:2]=2[C:21]2[CH:22]=[C:23]3[C:28](=[C:19]([F:18])[CH:20]=2)[N:27]2[C:29]([CH3:32])=[N:30][N:31]=[C:26]2[CH2:25][CH2:24]3)[CH2:10][CH2:9]1

Participants

6

Reactant 3

HCID 10340Sodium CarbonateHCID 717433633-Bromo-4-cyclopropyl-5-fluoropyridineHCID 89853586(9-Fluoro-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolin-7-yl)boronic acid

Product 1

HCID 717673277-(4-Cyclopropyl-5-fluoropyridin-3-yl)-9-fluoro-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 80711,2-DimethoxyethaneSolvent

Procedure

3-Bromo-4-cyclopropyl-5-fluoropyridine (462 mg, 2.14 mmol) was dissolved in a mixture of DME (3.55 mL) and water (3.55 mL). Sodium carbonate (226 mg, 2.14 mmol), (9-fluoro-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolin-7-yl)boronic acid (1-6, 176 mg, 0.71 mmol) and tetrakis triphenylphosphine palladium catalyst (4.11 mg, 3.6 mop were added. The mixture was deoxygenated under reduced pressure, flushed with nitrogen and heated under reflux for 18 h. After cooling to room temperature, ethyl acetate (10 mL) and water (10 mL) were added and the organic layer was separated. The water phase was extracted with ethyl acetate (2×10 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered over a short plug of Celite® and evaporated under reduced pressure. The crude compound was purified using preparative thin layer chromatography (ethyl acetate/ethanol 6:4) in order to yield the title compound as a white solid; 1H NMR (CD3SOCD3, 500 MHz) δ 8.49 (d, J=2.5 Hz, 1H), 8.35 (s, 1H), 7.60 (dd, J=1.8, 12.0 Hz, 1H), 7.52 (d, J=1.8 Hz, 1H), 3.80 (br. s, 4H), 2.54-2.52 (m, 3H), 1.96-1.95 (m, 1H), 0.89-0.87 (m, 2H), 0.68-0.67 (m, 2H); MS (ESI): m/z=338.97 [M+H]+.

Workup

  1. customThe mixture was deoxygenated under reduced pressure
  2. customflushed with nitrogen
  3. temperatureheated
  4. temperatureunder reflux for 18 h
  5. additionethyl acetate (10 mL) and water (10 mL) were added
  6. customthe organic layer was separated
  7. extractionThe water phase was extracted with ethyl acetate (2×10 mL)
  8. washThe combined organic phases were washed with brine
  9. dry with materialdried over Na2SO4
  10. filtrationfiltered over a short plug of Celite®
  11. customevaporated under reduced pressure
  12. customThe crude compound was purified

Sources & evidence

ORD record
ord-7ede33137a2a471990fd907b9003cc96
Source dataset
uspto-grants-2016_03
Patent number
US09278093B2

Reaction notes

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