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

HRID 662008Notes

Reaction equation

HRID 662008 reaction equation
Br[C:2]1[CH:3]=[C:4]([CH2:9][NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([NH:21][CH2:22][C:23]3[C:24]([NH:36][CH:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[C:25]4[CH:33]=[N:32][N:31]([CH2:34][CH3:35])[C:26]4=[N:27][C:28]=3[CH2:29][CH3:30])=[O:20])[N:14]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].[CH:43]([C:45]1[CH:46]=[C:47](B(O)O)[CH:48]=[CH:49][CH:50]=1)=[O:44].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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]>[CH2:34]([N:31]1[C:26]2=[N:27][C:28]([CH2:29][CH3:30])=[C:23]([CH2:22][NH:21][C:19]([C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([C:11]([NH:10][CH2:9][C:4]4[CH:3]=[C:2]([C:49]5[CH:48]=[CH:47][CH:46]=[C:45]([CH:43]=[O:44])[CH:50]=5)[C:7]([F:8])=[CH:6][CH:5]=4)=[O:12])[N:14]=3)=[O:20])[C:24]([NH:36][CH:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[C:25]2[CH:33]=[N:32]1)[CH3:35]

Participants

7

Reactant 3

HCID 10340Sodium CarbonateHCID 27343563-Formylphenylboronic acidHCID 57819367N-[(3-bromo-4-fluorophenyl)methyl]-N'-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide

Product 1

HCID 57819371N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N'-[(6-fluoro-3'-formyl-3-biphenylyl)methyl]-2,6-pyridinedicarboxamide

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of N-[(3-bromo-4-fluorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide (187 mg, 0.293 mmol), (3-formylphenyl)boronic acid (43.9 mg, 0.293 mmol), Na2CO3 (93 mg, 0.879 mmol) and PdCl2(dppf) (21.43 mg, 0.029 mmol) was diluted in a mixture of 1,4-dioxane (9 mL) and water (3 mL) in a 20 mL Biotage microwave reaction tube. The mixture was degassed by bubbling argon through it for 5 minutes and it was then heated in a Biotage microwave at normal absorption for 10 min at 100° C. The crude mixture was filtered through a PL-Thiol MP SPE+ and then washed with ethyl acetate. The combined organic layers were washed with water and brine. The organic layer was concentrated under vacuum to give a crude residue. It was then purified with flash chromatography eluting with 0 to 100% ethyl acetate in dichloromethane (product came out at 70% ethyl acetate in DCM). The product fractions were combined and concentrated under vacuum to give N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(6-fluoro-3′-formyl-3-biphenylyl)methyl]-2,6-pyridinedicarboxamide as an yellowish oil. LC-MS m/z 664.5 (M+H)+, 0.89 min (ret time).

Workup

  1. customThe mixture was degassed
  2. customby bubbling argon through it for 5 minutes
  3. filtrationThe crude mixture was filtered through a PL-Thiol MP SPE+
  4. washwashed with ethyl acetate
  5. washThe combined organic layers were washed with water and brine
  6. concentrationThe organic layer was concentrated under vacuum
  7. customto give a crude residue
  8. customIt was then purified with flash chromatography
  9. washeluting with 0 to 100% ethyl acetate in dichloromethane (product
  10. concentrationconcentrated under vacuum

Sources & evidence

ORD record
ord-7a7fa2f13fb8457a8662d6528ff3d744
Source dataset
uspto-grants-2011_12
Patent number
US08084449B2

Reaction notes

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