Ethanol → 4-(4-(3,3-difluoroazetidin-1-yl)pyrimidin-5-yl)-1-(2,4-difluorophenyl)-1H-pyrazolo[3,4-b]pyridine

HRID 1186830Notes

Reaction equation

HRID 1186830 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2=[N:14][CH:15]=[CH:16][C:17](B(O)O)=[C:12]2[CH:11]=[N:10]1.[F:21][C:22]1([F:33])[CH2:25][N:24]([C:26]2[C:31](I)=[CH:30][N:29]=[CH:28][N:27]=2)[CH2:23]1.C(O)C.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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:33][C:22]1([F:21])[CH2:23][N:24]([C:26]2[C:31]([C:17]3[CH:16]=[CH:15][N:14]=[C:13]4[N:9]([C:3]5[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=5[F:1])[N:10]=[CH:11][C:12]=34)=[CH:30][N:29]=[CH:28][N:27]=2)[CH2:25]1

Participants

8

Reactant 4

HCID 702EthanolHCID 10340Sodium CarbonateHCID 666681771-(2,4-difluorophenyl)-1H-pyrazolo[3,4-b]pyridin-4-ylboronic acidHCID 866901814-(3,3-Difluoroazetidin-1-yl)-5-iodopyrimidine

Product 1

HCID 680585154-(4-(3,3-difluoroazetidin-1-yl)pyrimidin-5-yl)-1-(2,4-difluorophenyl)-1H-pyrazolo[3,4-b]pyridine

Reagents, catalysts & solvents 3

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

Conditions

Temperature
90 °C

Procedure

To a solution of Intermediate 63A (35.7 mg, 0.1 mmol) and Intermediate 102A (44.6 mg, 0.150 mmol) in a mixture of DME (1 mL), ethanol (0.5 mL) and water (0.5 mL) was added Na2CO3 (0.042 g, 0.400 mmol). This suspension was degassed with a stream of N2 for 10 minutes and then tetrakis(triphenylphosphine)palladium(0) (5.78 mg, 5.00 mmol) was added followed by degassing for 10 minutes. The tube was then sealed, heated at 90° C. for 14 hours, and cooled to room temperature. The contents of the tube were diluted with MeOH, filtered, rinsed with MeOH, and concentrated to a brown sludge. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of Example 103 was 6.0 mg, and its purity was approximately 100%. LC/MS (condition C): ret time=1.52 min, MS (ES): m/z=401.01 [M+H]+.

Workup

  1. customThis suspension was degassed with a stream of N2 for 10 minutes
  2. customby degassing for 10 minutes
  3. customThe tube was then sealed
  4. temperaturecooled to room temperature
  5. additionThe contents of the tube were diluted with MeOH
  6. filtrationfiltered
  7. washrinsed with MeOH
  8. concentrationconcentrated to a brown sludge
  9. customThe crude material was purified via preparative LC/MS with the following conditions
  10. customa 5-minute hold
  11. additionFractions containing the desired product
  12. customdried via centrifugal evaporation
  13. customtime=1.52 min, MS (ES)

Sources & evidence

ORD record
ord-a2ff90936b924231aa3f88b5228b9534
Source dataset
uspto-grants-2014_03
Patent number
US08673922B2

Reaction notes

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