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

HRID 662006Notes

Reaction equation

HRID 662006 reaction equation
Br[C:2]1[CH:3]=[C:4]([CH2:8][NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([NH:20][CH2:21][C:22]3[C:23]([NH:35][CH:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[C:24]4[CH:32]=[N:31][N:30]([CH2:33][CH3:34])[C:25]4=[N:26][C:27]=3[CH2:28][CH3:29])=[O:19])[N:13]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH:42]([C:44]1[CH:45]=[C:46](B(O)O)[CH:47]=[CH:48][CH:49]=1)=[O:43].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]>[CH2:33]([N:30]1[C:25]2=[N:26][C:27]([CH2:28][CH3:29])=[C:22]([CH2:21][NH:20][C:18]([C:14]3[CH:15]=[CH:16][CH:17]=[C:12]([C:10]([NH:9][CH2:8][C:4]4[CH:3]=[C:2]([C:48]5[CH:47]=[CH:46][CH:45]=[C:44]([CH:42]=[O:43])[CH:49]=5)[CH:7]=[CH:6][CH:5]=4)=[O:11])[N:13]=3)=[O:19])[C:23]([NH:35][CH:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[C:24]2[CH:32]=[N:31]1)[CH3:34]

Participants

7

Reactant 3

HCID 10340Sodium CarbonateHCID 27343563-Formylphenylboronic acidHCID 57819389N-[(3-bromophenyl)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 57819366N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N'-[(3'-formyl-3-biphenylyl)methyl]-2,6-pyridinedicarboxamideYield 44.5%

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-bromophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide (600 mg, 0.967 mmol), (3-formylphenyl)boronic acid (188 mg, 1.257 mmol), Na2CO3 (307 mg, 2.90 mmol) and PdCl2(dppf) (70.7 mg, 0.097 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 30 min at 100° C. The crude mixture was filtered through a PL-Thiol MP SPE+ and was then washed with ethyl acetate and saturated NaHCO3. The organic layer was concentrated under vacuum to obtain the crude residue. It was purified with Gilson HPLC (with 0.1% TFA in the solvent) eluting with 15 to 80% CH3CN in water in a flow rate of 20 mL/min. The product fractions were dried under EZ2 Genevac and then combined to give N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-3-biphenylyl)methyl]-2,6-pyridinedicarboxamide as a solid (278 mg, 44.5%). LC-MS m/z 646.1 (M+H)+, 0.91 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. washwas then washed with ethyl acetate and saturated NaHCO3
  5. concentrationThe organic layer was concentrated under vacuum
  6. customto obtain the crude residue
  7. customIt was purified with Gilson HPLC (with 0.1% TFA in the solvent)
  8. washeluting with 15 to 80% CH3CN in water in a flow rate of 20 mL/min
  9. customThe product fractions were dried under EZ2 Genevac

Sources & evidence

ORD record
ord-96adceb5fb494fcda21bbac2e98c26f9
Source dataset
uspto-grants-2011_12
Patent number
US08084449B2

Reaction notes

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