Cesium carbonate → ethyl 5-[2-fluoro-4-(2-methoxy-4,6-dimethylpyridin-3-yl)phenyl]-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carboxylate

HRID 1043936Notes

Reaction equation

HRID 1043936 reaction equation
Br[C:2]1[C:3]([O:10][CH3:11])=[N:4][C:5]([CH3:9])=[CH:6][C:7]=1[CH3:8].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]([CH:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)[N:37]=[CH:36][C:35]=1[C:45]([O:47][CH2:48][CH3:49])=[O:46].BrC1C(C)=CC(C#N)=NC=1C>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:3]([O:10][CH3:11])=[N:4][C:5]([CH3:9])=[CH:6][C:7]=2[CH3:8])[CH:22]=[CH:21][C:20]=1[C:34]1[N:38]([CH:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)[N:37]=[CH:36][C:35]=1[C:45]([O:47][CH2:48][CH3:49])=[O:46]

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 866863313-Bromo-2-methoxy-4,6-dimethylpyridineHCID 866863465-Bromo-4,6-dimethylpicolinonitrileHCID 86686364ethyl 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carboxylate

Product 1

HCID 86686363ethyl 5-[2-fluoro-4-(2-methoxy-4,6-dimethylpyridin-3-yl)phenyl]-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carboxylate

Reagents, catalysts & solvents 3

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

Procedure

Water (5 mL), 3-bromo-2-methoxy-4,6-dimethylpyridine obtained in Preparation Example 26 (784 mg), Pd(PPh3)4 (380 mg) and cesium carbonate (2.36 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-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carboxylate obtained in Preparation Example 3 (2.04 g) in 1,4-dioxane (20 mL), and the reaction mixture was reacted at 110° C. for two hours in a nitrogen atmosphere. The reaction mixture was returned to room temperature and then filtered through Celite™. The filtrate was concentrated under reduced pressure. Ethyl acetate (100 mL) and water (100 mL) were added to the residue. The aqueous layer was extracted with ethyl acetate (50 mL×2). The combined organic layers were dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate/n-heptane, 10% to 23%). The title compound obtained by the same method (578 mg) was combined, and the combined product was purified again by silica gel column chromatography (ethyl acetate/n-heptane, 50% to 70%) to give the title compound (2.07 g).

Workup

  1. customthe reaction mixture was reacted at 110° C. for two hours in a nitrogen atmosphere
  2. customwas returned to room temperature
  3. filtrationfiltered through Celite™
  4. concentrationThe filtrate was concentrated under reduced pressure
  5. additionEthyl acetate (100 mL) and water (100 mL) were added to the residue
  6. extractionThe aqueous layer was extracted with ethyl acetate (50 mL×2)
  7. dry with materialThe combined organic layers were dried over anhydrous magnesium sulfate
  8. filtrationfiltered
  9. concentrationthe filtrate was concentrated under reduced pressure
  10. customThe residue was purified by NH silica gel column chromatography (ethyl acetate/n-heptane, 10% to 23%)

Sources & evidence

ORD record
ord-9e8811eff6f9435faf9ecca372ad3218
Source dataset
uspto-grants-2013_10
Patent number
US08563565B2

Reaction notes

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