Trifluoroacetic acid → N-[(5-Chloro-3'-{[(3S)-3-methyl-1-piperazinyl]methyl}-3-biphenylyl)methyl]-N'-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide

HRID 564593Notes

Reaction equation

HRID 564593 reaction equation
[CH3:1][C@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11](B3OC(C)(C)C(C)(C)O3)[CH:10]=2)[CH2:5][CH2:4][N:3]1C(OC(C)(C)C)=O.Br[C:32]1[CH:33]=[C:34]([CH2:39][NH:40][C:41]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([C:49]([NH:51][CH2:52][C:53]3[C:54]([NH:66][CH:67]4[CH2:72][CH2:71][O:70][CH2:69][CH2:68]4)=[C:55]4[CH:63]=[N:62][N:61]([CH2:64][CH3:65])[C:56]4=[N:57][C:58]=3[CH2:59][CH3:60])=[O:50])[CH:44]=2)=[O:42])[CH:35]=[C:36]([Cl:38])[CH:37]=1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)C(O)=O>O1CCOCC1.O.C(Cl)Cl.CS(C)=O.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>[Cl:38][C:36]1[CH:35]=[C:34]([CH2:39][NH:40][C:41]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([C:49]([NH:51][CH2:52][C:53]3[C:54]([NH:66][CH:67]4[CH2:72][CH2:71][O:70][CH2:69][CH2:68]4)=[C:55]4[CH:63]=[N:62][N:61]([CH2:64][CH3:65])[C:56]4=[N:57][C:58]=3[CH2:59][CH3:60])=[O:50])[CH:44]=2)=[O:42])[CH:33]=[C:32]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([CH2:8][N:6]3[CH2:5][CH2:4][NH:3][C@@H:2]([CH3:1])[CH2:7]3)[CH:10]=2)[CH:37]=1

Participants

10

Reactant 4

HCID 6422Trifluoroacetic acidHCID 11430Potassium CarbonateHCID 578132571,1-dimethylethyl (2S)-2-methyl-4-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-1-piperazinecarboxylateHCID 57813347HCID 57813347, compound

Product 1

HCID 57813491N-[(5-Chloro-3'-{[(3S)-3-methyl-1-piperazinyl]methyl}-3-biphenylyl)methyl]-N'-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide

Reagents, catalysts & solvents 5

HCID 178418397HCID 178418397, compoundCatalystHCID 679Dimethyl SulfoxideSolventHCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent

Procedure

1,1-Dimethylethyl (2S)-2-methyl-4-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-1-piperazinecarboxylate (24.98 mg, 0.060 mmol), N-[(3-bromo-5-chlorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (39.2 mg, 0.06 mmol), potassium carbonate (0.025 g, 0.18 mmol), and Pd(Ph3P)4 (3.47 mg, 3.00 μmol) were added to a 0.5-2 mL Biotage microwave vial in 1,4-dioxane (1.5 mL) and water (0.5 mL). The vial was capped and the mixture microwaved at normal power in the SmithCreator microwave at 100° C. for 15 min. LC-MS indicated complete reaction. The crude product was partitioned between EtOAc (30 mL) and water (10 mL). The phases were separated, and the organic washed with brine, dried over anhydrous Na2SO4 filtered and concentrated to give the protected product. This was taken up in DCM (1.8 mL) and treated with trifluoroacetic acid (0.2 mL). The mixture was stirred under argon for 5 h. LC-MS indicated complete reaction. Solvents were pumped off and the residue taken up in DMSO and purified on the Gilson with the TFA system. This was converted to the free base by taking the residue up in EtOAc (30 mL) and 2.5 N NaOH (5 mL). The phases were separated and the organic phase washed with 2.5 N NaOH (3×5 mL) and then with brine (2×5 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated to give the title compound as a white solid. LC-MS m/z 763.1 (M+H)+, 1.67 min (ret time); mp 119-121° C. Analytical HPLC shows 100% purity, (ret time 10.534 min).

Workup

  1. customThe vial was capped
  2. customthe mixture microwaved at normal power in the SmithCreator microwave at 100° C. for 15 min
  3. customreaction
  4. customThe crude product was partitioned between EtOAc (30 mL) and water (10 mL)
  5. customThe phases were separated
  6. washthe organic washed with brine
  7. dry with materialdried over anhydrous Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customto give the protected product
  11. customreaction
  12. custompurified on the Gilson with the TFA system
  13. customThe phases were separated
  14. washthe organic phase washed with 2.5 N NaOH (3×5 mL)
  15. dry with materialThe organic phase was dried over anhydrous Na2SO4
  16. filtrationfiltered
  17. concentrationconcentrated

Sources & evidence

ORD record
ord-4c7980375e5f4012b9553caf1458e090
Source dataset
uspto-grants-2011_11
Patent number
US08067408B2

Reaction notes

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