Cesium carbonate → 7-(2-methoxy-4,6-dimethylpyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one

HRID 1043935Notes

Reaction equation

HRID 1043935 reaction equation
COC1C=C(OC)C=CC=1CN1C2C=C(B3OC(C)(C)C(C)(C)O3)C=CC=2C2N(C3CCOCC3)N=CC=2C1=O.ClC1C(OC)=NC(C)=CC=1C.C(=O)([O-])[O-].[Cs+].[Cs+].COC1C=C(OC)C=CC=1C[N:63]1[C:72]2[CH:71]=[C:70]([C:73]3[C:74]([O:81][CH3:82])=[N:75][C:76]([CH3:80])=[CH:77][C:78]=3[CH3:79])[CH:69]=[CH:68][C:67]=2[C:66]2[N:83]([CH:86]3[CH2:91][CH2:90][O:89][CH2:88][CH2:87]3)[N:84]=[CH:85][C:65]=2[C:64]1=[O:92].COC1C=C(OC)C=CC=1CN1C2C=CC=CC=2C2N(C3CCOCC3)N=CC=2C1=O>O1CCOCC1.C(O)(C(F)(F)F)=O.O>[CH3:82][O:81][C:74]1[C:73]([C:70]2[CH:69]=[CH:68][C:67]3[C:66]4[N:83]([CH:86]5[CH2:91][CH2:90][O:89][CH2:88][CH2:87]5)[N:84]=[CH:85][C:65]=4[C:64](=[O:92])[NH:63][C:72]=3[CH:71]=2)=[C:78]([CH3:79])[CH:77]=[C:76]([CH3:80])[N:75]=1

Participants

9

Reactant 5

HCID 10796Cesium carbonateHCID 866863293-Chloro-2-methoxy-4,6-dimethylpyridineHCID 866863605-(2,4-dimethoxybenzyl)-1-(tetrahydro-2H-pyran-4-yl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-oneHCID 866863615-(2,4-dimethoxybenzyl)-7-(2-methoxy-4,6-dimethylpyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-oneHCID 866863625-(2,4-dimethoxybenzyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one

Product 1

HCID 1362539837-(2-methoxy-4,6-dimethylpyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6422Trifluoroacetic acidSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
65 °C

Procedure

5-(2,4-dimethoxybenzyl)-1-(tetrahydro-2H-pyran-4-yl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one (100 mg) obtained in Preparation Example 1(5) was dissolved in 1,4-dioxane (4 mL). 3-chloro-2-methoxy-4,6-dimethylpyridine obtained in Preparation Example 25 (472 mg), [(t-Bu)2P(OH)]2PdCl2 (4.6 mg), cesium carbonate (119 mg) and water (1 mL) were added to the solution, and the mixture was reacted using a microwave reactor at 130° C. for four hours. The reaction mixture was extracted with DCM. The organic layer was washed with brine and dried over sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 50% to 100%) to give a 1:1 mixture of 5-(2,4-dimethoxybenzyl)-7-(2-methoxy-4,6-dimethylpyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one and 5-(2,4-dimethoxybenzyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one (76 mg). The mixture (76 mg) was dissolved in TFA (1.5 mL), and the mixture was stirred at 65° C. for three hours. The reaction mixture was concentrated under reduced pressure. DCM and a saturated aqueous sodium bicarbonate solution were added to the resulting residue, followed by extraction with DCM. The organic layer was washed with brine and dried over sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 50% to 100%) to give the title compound (22 mg).

Workup

  1. additionwere added to the solution
  2. customthe mixture was reacted
  3. customat 130° C.
  4. customfor four hours
  5. extractionThe reaction mixture was extracted with DCM
  6. washThe organic layer was washed with brine
  7. dry with materialdried over sodium sulfate
  8. customThe desiccant was removed by filtration
  9. concentrationthe filtrate was concentrated under reduced pressure
  10. customThe resulting residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 50% to 100%)
  11. customto give
  12. concentrationThe reaction mixture was concentrated under reduced pressure
  13. additionDCM and a saturated aqueous sodium bicarbonate solution were added to the resulting residue
  14. extractionfollowed by extraction with DCM
  15. washThe organic layer was washed with brine
  16. dry with materialdried over sodium sulfate
  17. customThe desiccant was removed by filtration
  18. concentrationthe filtrate was concentrated under reduced pressure
  19. customThe resulting residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 50% to 100%)

Sources & evidence

ORD record
ord-55d9fb2256854f76b8164dbbeb5768a1
Source dataset
uspto-grants-2013_10
Patent number
US08563565B2

Reaction notes

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