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

HRID 662122
Notes
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Reaction equation

HRID 662122 reaction equation
Br[C:2]1[CH:3]=[C:4]([CH2:10][NH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([NH:22][CH2:23][C:24]3[C:25]([NH:37][CH:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[C:26]4[CH:34]=[N:33][N:32]([CH2:35][CH3:36])[C:27]4=[N:28][C:29]=3[CH2:30][CH3:31])=[O:21])[N:15]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:44][N:45]1[CH2:50][CH2:49][CH:48]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[C:54](B3OC(C)(C)C(C)(C)O3)[CH:53]=2)[CH2:47][CH2:46]1.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]>[CH2:35]([N:32]1[C:27]2=[N:28][C:29]([CH2:30][CH3:31])=[C:24]([CH2:23][NH:22][C:20]([C:16]3[CH:17]=[CH:18][CH:19]=[C:14]([C:12]([NH:11][CH2:10][C:4]4[CH:3]=[C:2]([C:56]5[CH:55]=[CH:54][CH:53]=[C:52]([CH2:51][CH:48]6[CH2:49][CH2:50][N:45]([CH3:44])[CH2:46][CH2:47]6)[CH:57]=5)[C:7]([O:8][CH3:9])=[CH:6][CH:5]=4)=[O:13])[N:15]=3)=[O:21])[C:25]([NH:37][CH:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[C:26]2[CH:34]=[N:33]1)[CH3:36]
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 3

HCID 10340Sodium CarbonateHCID 578134541-Methyl-4-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}piperidineHCID 57819364N-{[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}-2,6-pyridinedicarboxamide

Product 1

HCID 44193531
N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N'-({6-(methyloxy)-3'-[(1-methyl-4-piperidinyl)methyl]-3-biphenylyl}methyl)-2,6-pyridinedicarboxamide
Yield 12.9%

Reagents, catalysts & solvents 3

HCID 44119782Bis(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-(methyloxy)phenyl]methyl}-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide (50 mg, 0.077 mmol), 1-methyl-4-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}piperidine (30.8 mg, 0.077 mmol), Na2CO3 (24.44 mg, 0.231 mmol) and PdCl2(dppf) (5.62 mg, 7.69 μmol) was diluted in a mixture of 1,4-dioxane (3 mL) and water (1 mL) in a 2-5 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 minutes at 100° C. The crude mixture was filtered through a PL-Thiol MP SPE+ and was then washed with ethyl acetate and water. The organic layer was concentrated under vacuum to obtain a crude residue. It was purified with a Gilson HPLC (with 0.1% TFA in the solvents), eluting with 10 to 70% CH3CN in water at a flow rate of 20 mL/min. The product fractions were combined and converted to the free base with 1 N NaOH, and the basified solution was extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and then 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-(methyloxy)-3′-[(1-methyl-4-piperidinyl)methyl]-3-biphenylyl}methyl)-2,6-pyridinedicarboxamide as a solid (7.5 mg, 12.9%). LC-MS m/z 759 (M+H)+, 0.77 min (ret time); 1H NMR (400 MHz, CD3OD) δ 1.22-1.29 (m, 5H) 1.39 (t, J=7.15 Hz, 3H) 1.49-1.76 (m, 5H) 1.90-1.97 (m, 2H) 1.99-2.05 (m, 2H) 2.23 (s, 3H) 2.51 (d, J=7.03 Hz, 2H) 2.78-2.84 (m, 2H) 2.99 (q, J=7.53 Hz, 2H) 3.61 (td, J=11.42, 2.51 Hz, 2H) 3.74 (s, 3H) 3.90-4.02 (m, 2H) 4.12-4.19 (m, 1H) 4.40 (q, J=7.19 Hz, 2H) 4.58 (s, 2H) 4.74 (s, 2H) 6.97 (d, J=8.53 Hz, 1H) 7.01-7.08 (m, 1H) 7.16-7.32 (m, 5H) 7.98 (s, 1H) 8.15 (t, J=7.78 Hz, 1H) 8.28 (dd, J=7.91, 1.13 Hz, 1H) 8.36 (dd, J=7.78, 1.25 Hz, 1H).

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 water
  5. concentrationThe organic layer was concentrated under vacuum
  6. customto obtain a crude residue
  7. customIt was purified with a Gilson HPLC (with 0.1% TFA in the solvents),
  8. washeluting with 10 to 70% CH3CN in water at a flow rate of 20 mL/min
  9. extractionthe basified solution was extracted with ethyl acetate twice
  10. washThe combined organic layers were washed with brine
  11. dry with materialdried over sodium sulfate
  12. filtrationfiltered
  13. concentrationconcentrated under vacuum

Sources & evidence

ORD record
ord-e7a4264f93ce4b01a5a0dbefa74a0bb0
Source dataset
uspto-grants-2011_12
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08084449B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes