Potassium Carbonate → N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N'-{[3'-formyl-6-(methyloxy)-3-biphenylyl]methyl}-5-methyl-1,3-benzenedicarboxamide

HRID 564424Notes

Reaction equation

HRID 564424 reaction equation
Br[C:2]1[CH:3]=[C:4]([CH2:10][NH:11][C:12]([C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([C:21]([NH:23][CH2:24][C:25]3[C:26]([NH:38][CH:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)=[C:27]4[CH:35]=[N:34][N:33]([CH2:36][CH3:37])[C:28]4=[N:29][C:30]=3[CH2:31][CH3:32])=[O:22])[CH:15]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH:45]([C:47]1[CH:48]=[C:49](B(O)O)[CH:50]=[CH:51][CH:52]=1)=[O:46].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C(Cl)Cl.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>[CH2:36]([N:33]1[C:28]2=[N:29][C:30]([CH2:31][CH3:32])=[C:25]([CH2:24][NH:23][C:21]([C:16]3[CH:17]=[C:18]([CH3:20])[CH:19]=[C:14]([C:12]([NH:11][CH2:10][C:4]4[CH:3]=[C:2]([C:51]5[CH:50]=[CH:49][CH:48]=[C:47]([CH:45]=[O:46])[CH:52]=5)[C:7]([O:8][CH3:9])=[CH:6][CH:5]=4)=[O:13])[CH:15]=3)=[O:22])[C:26]([NH:38][CH:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[C:27]2[CH:35]=[N:34]1)[CH3:37]

Participants

8

Reactant 3

HCID 11430Potassium CarbonateHCID 27343563-Formylphenylboronic acidHCID 57813272N-{[3-Bromo-4-(methyloxy)phenyl]methyl}-N'-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-5-methyl-1,3-benzenedicarboxamide

Product 1

HCID 57813428N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N'-{[3'-formyl-6-(methyloxy)-3-biphenylyl]methyl}-5-methyl-1,3-benzenedicarboxamideYield 64.4%

Reagents, catalysts & solvents 4

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

Procedure

N-{[3-Bromo-4-(methyloxy)phenyl]methyl}-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-5-methyl-1,3-benzenedicarboxamide (900 mg, 1.356 mmol), (3-formylphenyl)boronic acid (203 mg, 1.356 mmol), potassium carbonate (562 mg, 4.07 mmol), and Pd(Ph3P)4 (78 mg, 0.068 mmol) were divided into 3 portions and added to three 2-5 mL Biotage microwave vials in 1,4-dioxane (3 mL) and water (1 mL). The vials were capped and the mixtures were microwaved at normal power in the Emrys Optimizer at 100° C. for 15 min. The combined crude product was partitioned between EtOAc (75 mL) and water (20 mL). The phases were separated and the organic phase was washed with water (2×20 mL), brine (20 mL), dried over anhydrous Na2SO4, filtered and evaporated to give the crude residue. It was taken up in DCM and absorbed on Isolute® Sorbent and purified by CombiFlash using an 80 g silica column eluted with 0-10% MeOH/DCM. The product fractions were combined and concentrated to give N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-{[3′-formyl-6-(methyloxy)-3-biphenylyl]methyl}-5-methyl-1,3-benzenedicarboxamide (632 mg, 0.873 mmol, 64.3% yield) as a white solid. LC-MS m/z 689.8 (M+H)+, 0.95 min (ret time); mp 117-119° C.

Workup

  1. customThe vials were capped
  2. customthe mixtures were microwaved at normal power in the Emrys Optimizer at 100° C. for 15 min
  3. customwas partitioned between EtOAc (75 mL) and water (20 mL)
  4. customThe phases were separated
  5. washthe organic phase was washed with water (2×20 mL), brine (20 mL)
  6. dry with materialdried over anhydrous Na2SO4
  7. filtrationfiltered
  8. customevaporated
  9. customto give the crude residue
  10. customabsorbed on Isolute® Sorbent
  11. custompurified by CombiFlash
  12. washeluted with 0-10% MeOH/DCM
  13. concentrationconcentrated

Sources & evidence

ORD record
ord-5b7db76ec8824628bef9c4cd15e00e99
Source dataset
uspto-grants-2011_11
Patent number
US08067408B2

Reaction notes

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