3-Bromo-6-methoxy-2,4-dimethylpyridine → ethyl 5-(2,5-difluoro-4-(6-methoxy-2,4-dimethylpyridin-3-yl)phenyl)-1-[(S)-tetrahydrofuran-3-yl]-1H-pyrazole-4-carboxylate

HRID 1043966Notes

Reaction equation

HRID 1043966 reaction equation
[F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[C:5]([F:17])=[CH:4][C:3]=1[C:18]1[N:22]([C@H:23]2[CH2:27][CH2:26][O:25][CH2:24]2)[N:21]=[CH:20][C:19]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29].Br[C:34]1[C:35]([CH3:43])=[N:36][C:37]([O:41][CH3:42])=[CH:38][C:39]=1[CH3:40].F.[K]>COCCOC.O.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>[F:1][C:2]1[CH:7]=[C:6]([C:34]2[C:35]([CH3:43])=[N:36][C:37]([O:41][CH3:42])=[CH:38][C:39]=2[CH3:40])[C:5]([F:17])=[CH:4][C:3]=1[C:18]1[N:22]([C@H:23]2[CH2:27][CH2:26][O:25][CH2:24]2)[N:21]=[CH:20][C:19]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29]

Participants

7

Reactant 3

HCID 112413813-Bromo-6-methoxy-2,4-dimethylpyridineHCID 53443437Potassium fluoride, 99%, spray-driedHCID 86686393ethyl 5-(2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-((S)-tetrahydrofuran-3-yl)-1H-pyrazole-4-carboxylate

Product 1

HCID 86686401ethyl 5-(2,5-difluoro-4-(6-methoxy-2,4-dimethylpyridin-3-yl)phenyl)-1-[(S)-tetrahydrofuran-3-yl]-1H-pyrazole-4-carboxylate

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
110 °C

Procedure

A mixture of ethyl 5-[2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-[(S)-tetrahydrofuran-3-yl]-1H-pyrazole-4-carboxylate synthesized in accordance with Example 53 (430 mg), 3-bromo-6-methoxy-2,4-dimethylpyridine obtained in Preparation Example 23 (223 mg), potassium hydrogen fluoride (254 mg), Pd(PPh3)4 (90 mg) and tripotassium phosphate n-hydrate (400 mg) in DME (8 mL) and water (2 mL) was heated under reflux at 110° C. for seven hours. The reaction mixture was cooled to room temperature and partitioned by adding ethyl acetate and brine. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated, and the residue was purified by NH silica gel column chromatography (ethyl acetate/n-heptane: 16% to 37% to 46%) and silica gel column chromatography (ethyl acetate/n-heptane: 28% to 49% to 54%) to give the title compound (144 mg). This compound was used for the next reaction without further purification.

Workup

  1. temperaturewas heated
  2. temperatureThe reaction mixture was cooled to room temperature
  3. custompartitioned
  4. additionby adding ethyl acetate and brine
  5. dry with materialThe organic layer was dried over anhydrous magnesium sulfate
  6. filtrationfiltered
  7. concentrationThe filtrate was concentrated
  8. customthe residue was purified by NH silica gel column chromatography (ethyl acetate/n-heptane: 16% to 37% to 46%) and silica gel column chromatography (ethyl acetate/n-heptane: 28% to 49% to 54%)

Sources & evidence

ORD record
ord-d211184adc2440468163b38df88f791a
Source dataset
uspto-grants-2013_10
Patent number
US08563565B2

Reaction notes

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