Sodium Bicarbonate → 3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

HRID 1909914Notes

Reaction equation

HRID 1909914 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11](=[O:21])[CH2:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[F:20])[CH2:6][CH2:5]2.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:46]1[C:54]2[C:49](=[N:50][CH:51]=[N:52][C:53]=2[NH2:55])[N:48]([CH3:56])[N:47]=1.C([O-])(O)=O.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O1CCOCC1>[F:20][C:14]1[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=1[CH2:12][C:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:46]3[C:54]4[C:49](=[N:50][CH:51]=[N:52][C:53]=4[NH2:55])[N:48]([CH3:56])[N:47]=3)=[CH:10][CH:9]=2)[CH2:5][CH2:6]1)=[O:21]

Participants

8

Reactant 5

HCID 516892Sodium BicarbonateHCID 517044Potassium AcetateHCID 2733548Bis(pinacolato)diboraneHCID 127789343-Bromo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amineHCID 668238625-bromo-1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indole

Product 1

HCID 534667253-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amineYield 83.8%

Reagents, catalysts & solvents 2

HCID 178418807HCID 178418807, compoundCatalyst2×HCID 312751,4-DioxaneSolvent

Procedure

To a mixture of 5-bromo-1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indole (160 mg, 0.454 mmol), bis(pinacolato)diboron (127 mg, 0.500 mmol), and potassium acetate (134 mg, 1.363 mmol) was added 1,4-dioxane (6 mL), and the mixture was degassed with N2 for 10 minutes. PdCl2(dppf)-CH2Cl2 adduct (18.55 mg, 0.023 mmol) was added, and the reaction mixture was stirred for 3 hours at 100 C in a sealed vessel. The reaction was cooled down to room temperature. 3-bromo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (104 mg, 0.454 mmol) and sat. aq. NaHCO3 (2 mL) were added, and N2 gas was bubbled through the mixture for 10 minutes. PdCl2(dppf)-CH2Cl2 adduct (18.55 mg, 0.023 mmol) was added, the vessel was sealed, and the reaction mixture was stirred overnight at 100 C (LCMS:N13207-34suzu). The mixture was allowed to cool to room temperature and poured onto water (˜150 mL). The resulting mixture was filtered, and the resulting solid was triturated with Et2O. To the solid in the filter was added a 90:10 mixture of CHCl3:CH3OH (˜7 mL), and the resulting mixture was filtered. The filtrate was injected into a 90 g SiO2 columns. Flash chromatography on SiO2 (gradient: 100% CHCl3 to 90:10:1 CHCl3:CH3OH:NH4OH) provided the title compound 3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (160 mg) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 3.29 (t, J=8.34 Hz, 2H), 3.94 (s, 3H), 3.97 (s, 2H), 4.30 (t, J=8.46 Hz, 2H), 7.14-7.31 (m, 3H), 7.44 (d, J=8.34 Hz, 1H), 7.53 (s, 1H), 8.14 (d, J=8.34 Hz, 1H), 8.25 (s, 1H)

Workup

  1. customthe mixture was degassed with N2 for 10 minutes
  2. customN2 gas was bubbled through the mixture for 10 minutes
  3. customthe vessel was sealed
  4. stirringthe reaction mixture was stirred overnight at 100 C (LCMS:N13207-34suzu)
  5. temperatureto cool to room temperature
  6. additionpoured onto water (˜150 mL)
  7. filtrationThe resulting mixture was filtered
  8. customthe resulting solid was triturated with Et2O
  9. additionTo the solid in the filter was added
  10. additiona 90:10 mixture of CHCl3
  11. filtrationCH3OH (˜7 mL), and the resulting mixture was filtered

Sources & evidence

ORD record
ord-259dbf1f544742c48fb441718def9cb2
Source dataset
uspto-grants-2013_12
Patent number
US08598156B2

Reaction notes

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