Cesium carbonate → ethyl 5-[2-fluoro-4-(2-methoxy-3,5-dimethylpyridin-4-yl)phenyl]-1-[(S)-tetrahydrofuran-3-yl]-1H-pyrazole-4-carboxylate

HRID 1043943Notes

Reaction equation

HRID 1043943 reaction equation
I[C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([O:9][CH3:10])[C:3]=1[CH3:11].C(=O)([O-])[O-].[Cs+].[Cs+].[F:18][C:19]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[CH:21][C:20]=1[C:34]1[N:38]([C@H:39]2[CH2:43][CH2:42][O:41][CH2:40]2)[N:37]=[CH:36][C:35]=1[C:44]([O:46][CH2:47][CH3:48])=[O:45].COC1C=C(OC)C=CC=1CN1C2C=C(B(O)O)C=CC=2C2N(C3CCOCC3)N=CC=2C1=O>O1CCOCC1.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>[F:18][C:19]1[CH:24]=[C:23]([C:2]2[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([O:9][CH3:10])[C:3]=2[CH3:11])[CH:22]=[CH:21][C:20]=1[C:34]1[N:38]([C@H:39]2[CH2:43][CH2:42][O:41][CH2:40]2)[N:37]=[CH:36][C:35]=1[C:44]([O:46][CH2:47][CH3:48])=[O:45]

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 86686332HCID 86686332, compoundHCID 86686369[5-(2,4-dimethoxybenzyl)-4-oxo-1-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-1H-pyrazolo[4,3-c]quinolin-7-yl]boronic acidHCID 86686374Ethyl (S)-5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-4-carboxylate

Product 1

HCID 86686373ethyl 5-[2-fluoro-4-(2-methoxy-3,5-dimethylpyridin-4-yl)phenyl]-1-[(S)-tetrahydrofuran-3-yl]-1H-pyrazole-4-carboxylate

Reagents, catalysts & solvents 3

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

Procedure

Water (170 mL), 4-iodo-2-methoxy-3,5-dimethylpyridine obtained in Preparation Example 29(3) (35.6 g), Pd(PPh3)4 (6.52 g) and cesium carbonate (110 g) were added to a solution of ethyl 5-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-[(S)-tetrahydrofuran-3-yl]-1H-pyrazole-4-carboxylate obtained in Preparation Example 6 (51.9 g) in 1,4-dioxane (500 mL), and the reaction mixture was reacted at 110° C. for six hours. The reaction mixture was returned to room temperature, and the organic layer was then separated. The organic layer was concentrated under reduced pressure. The aqueous layer, ethyl acetate (700 m) and water (100 mL) were added to the resulting residue, and the organic layer was separated. The aqueous layer was re-extracted with ethyl acetate (50 mL). The combined organic layers were sequentially washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate/n-heptane, 5% to 14%). The product was then purified again by NH silica gel column chromatography (ethyl acetate/n-heptane, 2% to 10%) to give the title compound (435 g).

Workup

  1. customthe reaction mixture was reacted at 110° C. for six hours
  2. customwas returned to room temperature
  3. customthe organic layer was then separated
  4. concentrationThe organic layer was concentrated under reduced pressure
  5. additionThe aqueous layer, ethyl acetate (700 m) and water (100 mL) were added to the resulting residue
  6. customthe organic layer was separated
  7. extractionThe aqueous layer was re-extracted with ethyl acetate (50 mL)
  8. washThe combined organic layers were sequentially washed with water and brine
  9. dry with materialdried over anhydrous magnesium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated under reduced pressure
  12. customThe residue was purified by NH silica gel column chromatography (ethyl acetate/n-heptane, 5% to 14%)
  13. customThe product was then purified again by NH silica gel column chromatography (ethyl acetate/n-heptane, 2% to 10%)

Sources & evidence

ORD record
ord-1359e80a76fa4846bb408d4126bd84d5
Source dataset
uspto-grants-2013_10
Patent number
US08563565B2

Reaction notes

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