Sodium Carbonate → (R)-4-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)benzonitrile

HRID 1890684Notes

Reaction equation

HRID 1890684 reaction equation
Br[C:2]1[N:6]2[N:7]=[C:8]([N:11]3[CH2:15][CH2:14][CH2:13][CH:12]3[C:16]3[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=3[F:23])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:30]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)#[N:31]>O1CCOCC1.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:23][C:17]1[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=1[C@H:12]1[CH2:13][CH2:14][CH2:15][N:11]1[C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:35]3[CH:36]=[CH:37][C:32]([C:30]#[N:31])=[CH:33][CH:34]=3)=[CH:3][N:4]=2)[N:7]=1

Participants

7

Reactant 3

HCID 10340Sodium CarbonateHCID 27343264-Cyanophenylboronic acidHCID 583354643-Bromo-6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine

Product 1

HCID 44520440(R)-4-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)benzonitrile

Reagents, catalysts & solvents 3

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

Conditions

Temperature
150 °C

Procedure

In step 6A-5, palladium tetrakis (25 mg, 0.02 mmol) was added to a solution of 3-bromo-6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine (6-6) (77 mg, 0.23 mmol), sodium carbonate (85 mg, 0.81 mmol), and 4-cyanophenylboronic acid (60 mg, 0.41 mmol) in 2 mL of dioxane and 0.5 mL of water contained in a microwave reaction tube. The resulting solution was heated in a microwave for 25 minutes at 150° C. and the yellow slurry was cooled to room temperature and filtered through a 0.2 μm nylon frit. The solvent was removed from the mother liquor and the remaining residue was reconstituted in methanol and further purified by preparative LC/MS. The desired fractions were dried to yield the desired product as a racemic mixture, which was then purified by chiral LC to yield (R)-4-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)benzonitrile (6-7) as a chiral pure white solid along with (S)-4-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)benzonitrile as a chiral pure white solid.

Workup

  1. customcontained in a microwave reaction tube
  2. temperaturethe yellow slurry was cooled to room temperature
  3. filtrationfiltered through a 0.2 μm nylon frit
  4. customThe solvent was removed from the mother liquor
  5. customfurther purified by preparative LC/MS
  6. customThe desired fractions were dried

Sources & evidence

ORD record
ord-957c63c8261a460b9428509544b2ea62
Source dataset
uspto-grants-2013_08
Patent number
US08507488B2

Reaction notes

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