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Boronic Acid → (3-Amino-2,6-difluoro-phenyl)-[5-(4-chlorophenyl)-1-(2,6-dichlorobenzoyl)pyrrolo[2,3-b]pyridin-3-yl]methanone

HRID 1747255
Notes
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Reaction equation

HRID 1747255 reaction equation
[NH2:1][C:2]1[C:3]([F:31])=[C:4]([C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17](Br)[CH:18]=3)[N:13]([C:21](=[O:30])[C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])[CH:12]=2)=[O:10])[C:5]([F:8])=[CH:6][CH:7]=1.B(O)O.C(=O)(O)[O-].[Na+]>CC1CCCO1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[C:3]([F:31])=[C:4]([C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:24]4[CH:23]=[CH:22][C:27]([Cl:28])=[CH:26][CH:25]=4)[CH:18]=3)[N:13]([C:21](=[O:30])[C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])[CH:12]=2)=[O:10])[C:5]([F:8])=[CH:6][CH:7]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 3

HCID 61668Boronic AcidHCID 516892Sodium BicarbonateHCID 72549401(3-(3-Amino-2,6-difluorobenzoyl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-1-yl)(2,6-dichlorophenyl)methanone

Product 1

HCID 72549402(3-Amino-2,6-difluoro-phenyl)-[5-(4-chlorophenyl)-1-(2,6-dichlorobenzoyl)pyrrolo[2,3-b]pyridin-3-yl]methanoneYield 74%

Reagents, catalysts & solvents 2

HCID 178418476
HCID 178418476, compound
Catalyst
HCID 73012-MethyltetrahydrofuranSolvent

Procedure

Under a nitrogen atmosphere, a 50-liter flask is charged with compound 5 (1.735 kg, 3.304 mol) prepared from Example 3 in 2-methyl-THF, boronic acid 6 (0.877 kg, 5.617 mol), PdCl2(PPh3)2 (0.116 kg, 0.165 mol) and an aqueous sodium bicarbonate (0.833 kg, 9.912 mol) solution (8.7 L). The reaction mixture is degassed and heated to reflux for 7 hrs and stirred at room temperature overnight. Compound 6 (129.0 g) and PdCl2(PPh3)2 (6.6 g) are added again and the reaction mixture is heated to reflux for another 5 hrs. Celite (1.735 kg) is added and the mixture is stirred for 30 minutes and then filtered through a pad of celite. The residue is washed with 2-methyl-THF. The organic layer is separated, washed with a 10% NaCl aqueous solution (4 L) for three times, further washed with a 20% NaCl aqueous solution, filtered, and dried over Na2SO4. The filtrate is concentrated by removing about 80-85% of solvent, added ethyl acetate (3.5 L) and stirred overnight. The mixture is filtered and washed with ethyl acetate (2×3.5 L) twice. Compound 7, is isolated after removing the solvents and drying at 45° C. for 48 hrs (2.765 kg, 74% yield).

Workup

  1. customThe reaction mixture is degassed
  2. temperatureheated
  3. temperatureto reflux for 7 hrs
  4. additionCompound 6 (129.0 g) and PdCl2(PPh3)2 (6.6 g) are added again
  5. temperaturethe reaction mixture is heated
  6. temperatureto reflux for another 5 hrs
  7. additionCelite (1.735 kg) is added
  8. stirringthe mixture is stirred for 30 minutes
  9. filtrationfiltered through a pad of celite
  10. washThe residue is washed with 2-methyl-THF
  11. customThe organic layer is separated
  12. washwashed with a 10% NaCl aqueous solution (4 L) for three times
  13. washfurther washed with a 20% NaCl aqueous solution
  14. filtrationfiltered
  15. dry with materialdried over Na2SO4
  16. concentrationThe filtrate is concentrated
  17. customby removing about 80-85% of solvent
  18. additionadded ethyl acetate (3.5 L)
  19. stirringstirred overnight
  20. filtrationThe mixture is filtered
  21. washwashed with ethyl acetate (2×3.5 L) twice

Sources & evidence

ORD record
ord-6019d77cf3a3444b8c1d8123e6d8e4de
Source dataset
uspto-grants-2015_10
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09150570B2

Reaction notes

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