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

HRID 1909956Notes

Reaction equation

HRID 1909956 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:53]([NH2:55])=[N:52][CH:51]=[N:50][C:49]=2[S:48][CH: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.CCOCC.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:53]([NH2:55])=[N:52][CH:51]=[N:50][C:49]=4[S:48][CH:47]=3)=[CH:10][CH:9]=2)[CH2:5][CH2:6]1)=[O:21]

Participants

9

Reactant 5

HCID 516892Sodium BicarbonateHCID 517044Potassium AcetateHCID 2733548Bis(pinacolato)diboraneHCID 668238625-bromo-1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indoleHCID 668238985-Bromothieno[2,3-D]pyrimidin-4-amine

Product 1

HCID 534671775-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}thieno[2,3-d]pyrimidin-4-amineYield 66.7%

Reagents, catalysts & solvents 3

HCID 178418807HCID 178418807, compoundCatalyst2×HCID 3283Diethyl EtherSolventHCID 312751,4-DioxaneSolvent

Procedure

To a mixture of 5-bromo-1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indole (150 mg, 0.426 mmol), bis(pinacolato)diboron (114 mg, 0.447 mmol), and potassium acetate (125 mg, 1.278 mmol) was added 1,4-dioxane (6 mL), and the mixture was degassed with N2 for 10 minutes. PdCl2(dppf)-CH2Cl2 adduct (17.39 mg, 0.021 mmol) was added, and the reaction mixture was stirred for 3 hours at 100 C into a sealed vessel. The reaction was cooled down to room temperature. 5-bromothieno[2,3-d]pyrimidin-4-amine (103 mg, 0.447 mmol) and sat. aq. NaHCO3 (2 mL) were added, and N2 gas was bubbled through the mixture for 10 minutes. PdCl2(dppf)-CH2Cl2 adduct (17.39 mg, 0.021 mmol) was added, the vessel was sealed, and the reaction mixture was stirred overnight at 100 C. The mixture was poured onto water and a precipitate was formed. The mixture was filtered, and the solid was taken up into a mixture of 20% CH3OH/CH2Cl2 mixture, and the resulting mixture was filtered, injected into a 90 g silica gel column, and purified via flash chromatography (gradient: 100% Hexanes to 100% EtOAc). The fractions containing the product were combined and concentrated to afford a solid. Trituration with Et2O afforded 5-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}thieno[2,3-d]pyrimidin-4-amine (120 mg) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 3.27 (t, 2H), 3.96 (s, 2H), 4.31 (t, J=8.46 Hz, 2H), 7.13-7.32 (m, 4H), 7.37 (s, 1H), 7.43 (s, 1H), 8.11 (d, J=8.08 Hz, 1H), 8.34 (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
  5. additionThe mixture was poured onto water
  6. customa precipitate was formed
  7. filtrationThe mixture was filtered
  8. additionthe solid was taken up into a mixture of 20% CH3OH/CH2Cl2 mixture
  9. filtrationthe resulting mixture was filtered
  10. custompurified via flash chromatography (gradient: 100% Hexanes to 100% EtOAc)
  11. additionThe fractions containing the product
  12. concentrationconcentrated
  13. customto afford a solid

Sources & evidence

ORD record
ord-3a42f10afff447d8a3cadd249baba8b5
Source dataset
uspto-grants-2013_12
Patent number
US08598156B2

Reaction notes

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