Cesium carbonate → (+/-)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one

HRID 1043942Notes

Reaction equation

HRID 1043942 reaction equation
COC1C=C(OC)C=CC=1C[N:6]1[C:15]2[CH:14]=[C:13](B3OC(C)(C)C(C)(C)O3)[CH:12]=[CH:11][C:10]=2[C:9]2[N:25]([CH:28]3[CH2:32][CH2:31][O:30][CH2:29]3)[N:26]=[CH:27][C:8]=2[C:7]1=[O:33].Cl.O1CC(NN)COCC1.Br[C:51]1[C:56]([CH3:57])=[CH:55][N:54]=[C:53]([O:58][CH3:59])[C:52]=1[CH3:60].C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.O1CCOCC1>[CH3:59][O:58][C:53]1[C:52]([CH3:60])=[C:51]([C:13]2[CH:12]=[CH:11][C:10]3[C:9]4[N:25]([CH:28]5[CH2:32][CH2:31][O:30][CH2:29]5)[N:26]=[CH:27][C:8]=4[C:7](=[O:33])[NH:6][C:15]=3[CH:14]=2)[C:56]([CH3:57])=[CH:55][N:54]=1

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 67811684HCID 67811684, compoundHCID 86686315(1,4-Dioxepan-6-yl)hydrazine hydrochlorideHCID 86686372HCID 86686372, compound

Product 1

HCID 136387812(+/-)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
70 °C

Procedure

A mixture of (±)-5-(2,4-dimethoxybenzyl)-1-(tetrahydrofuran-3-yl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one obtained in Preparation Example 5 (219 mg), 4-bromo-2-methoxy-3,5-dimethylpyridine obtained in Preparation Example 28 (134 mg), Pd(PPh3)4 (23.8 mg) and cesium carbonate (403 mg) was reacted in a mixed solvent of 1,4-dioxane (8 mL) and water (2 mL) using a microwave reactor at 130° C. for 70 minutes. The reaction mixture was cooled to mom temperature and then directly purified by silica gel column chromatography (ethyl acetate/n-heptane, 10% to 90%). The resulting coupling product was dissolved in TFA (4 mL), and the mixture was stirred at 70° C. for two hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. A saturated aqueous sodium bicarbonate solution was added to the residue, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM, 100%, then ethyl acetate/n-heptane, 50% to 100%) to give the title compound (78 mg).

Workup

  1. customat 130° C.
  2. customfor 70 minutes
  3. temperatureThe reaction mixture was cooled to mom temperature
  4. customdirectly purified by silica gel column chromatography (ethyl acetate/n-heptane, 10% to 90%)
  5. dissolutionThe resulting coupling product was dissolved in TFA (4 mL)
  6. temperatureThe reaction mixture was cooled to room temperature
  7. concentrationconcentrated under reduced pressure
  8. additionA saturated aqueous sodium bicarbonate solution was added to the residue
  9. extractionfollowed by extraction with ethyl acetate
  10. concentrationThe organic layer was concentrated under reduced pressure
  11. customthe residue was purified by silica gel column chromatography (DCM, 100%

Sources & evidence

ORD record
ord-93d182153a9848dbbb6ec4e66fd872d0
Source dataset
uspto-grants-2013_10
Patent number
US08563565B2

Reaction notes

Loading…