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

HRID 1909921Notes

Reaction equation

HRID 1909921 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.C([O-])(=O)C.[K+].Br[C:28]1[C:32]2[C:33]([NH2:37])=[N:34][CH:35]=[CH:36][C:31]=2[S:30][CH:29]=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.C(OCC)(=O)C.O.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:28]3[C:32]4[C:33]([NH2:37])=[N:34][CH:35]=[CH:36][C:31]=4[S:30][CH:29]=3)=[CH:10][CH:9]=2)[CH2:5][CH2:6]1)=[O:21]

Participants

9

Reactant 4

HCID 516892Sodium BicarbonateHCID 517044Potassium AcetateHCID 184507973-Bromothieno[3,2-c]pyridin-4-amineHCID 668238625-bromo-1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indole

Product 1

HCID 534676173-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}thieno[3,2-c]pyridin-4-amineYield 62.8%

Reagents, catalysts & solvents 4

HCID 178418807HCID 178418807, compoundCatalystHCID 962WaterSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

In a sealable tube, to 5-bromo-1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indole (0.700 g, 1.988 mmol), bispinacolatodiboron (0.606 g, 2.385 mmol) and potassium acetate (0.585 g, 5.96 mmol) was added 1,4-Dioxane (15 mL) and the mixture was degassed with N2 for 10 minutes. PdCl2(dppf)-CH2Cl2Adduct (0.081 g, 0.99 mmol) was added and the reaction mixture was sealed and stirred for 48 hours at 100° C. The mixture was cooled to room temperature and treated with 5 mL of water, 3-bromothieno[3,2-c]pyridin-4-amine (0.501 g, 2.186 mmol) and sodium bicarbonate (167 mg, 1.988 mmol). The mixture was degassed with N2 for 10 minutes. PdCl2(dppf)-CH2Cl2 adduct (0.085 g, 0.104 mmol) was added and the reaction mixture was stirred overnight at 100° C. The mixture was poured onto water and ethyl acetate, then filtered. The filtrate was poured into a separatory funnel. The organic layer was separated and the aqueous layer was further extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated. Purified by Analogix silica gel cartridge 25/40, eluting with a gradient of 0-100% EtOAc/hexane. The compound came out at 100% EtOAc in 10 minutes. The pure fractions with the compound were combined. The solvents were evaporated and dried to give an off-white solid (526 mg) of the title compound 3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}thieno[3,2-c]pyridin-4-amine. LC-MS (ES) m/z=422.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.11 (d, J=8.3 Hz, 1H) 7.82 (d, J=5.6 Hz, 1H) 7.42 (s, 1H) 7.35 (s, 1H) 7.12-7.31 (m, 5H) 5.41 (br. s., 2H) 4.31 (t, J=8.3 Hz, 2H) 3.96 (s, 2H) 3.23-3.31 (m, 2H).

Workup

  1. customthe mixture was degassed with N2 for 10 minutes
  2. customthe reaction mixture was sealed
  3. temperatureThe mixture was cooled to room temperature
  4. customThe mixture was degassed with N2 for 10 minutes
  5. stirringthe reaction mixture was stirred overnight at 100° C
  6. filtrationfiltered
  7. additionThe filtrate was poured into a separatory funnel
  8. customThe organic layer was separated
  9. extractionthe aqueous layer was further extracted with ethyl acetate
  10. washThe combined organic layers were washed with brine
  11. dry with materialdried (MgSO4)
  12. filtrationfiltered
  13. concentrationconcentrated
  14. customPurified by Analogix silica gel cartridge 25/40
  15. washeluting with a gradient of 0-100% EtOAc/hexane
  16. waitThe compound came out at 100% EtOAc in 10 minutes
  17. customThe solvents were evaporated
  18. customdried

Sources & evidence

ORD record
ord-dc596bc3b6df458fbda0c3cca8a38a7c
Source dataset
uspto-grants-2013_12
Patent number
US08598156B2

Reaction notes

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