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Sodium Carbonate → N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N1-({6-methyl-3'-[(1-methyl-4-piperidinyl)methyl]-3-biphenylyl}methyl)-1,1-cyclopropanedicarboxamide

HRID 657411
Notes
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Reaction equation

HRID 657411 reaction equation
Br[C:2]1[CH:3]=[C:4]([CH2:9][N:10]([CH2:19][C:20]2[C:21]([NH:33][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[C:22]3[CH:30]=[N:29][N:28]([CH2:31][CH3:32])[C:23]3=[N:24][C:25]=2[CH2:26][CH3:27])[C:11]([C:13]2([C:16]([NH2:18])=[O:17])[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:40][N:41]1[CH2:46][CH2:45][CH:44]([CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[C:50](B3OC(C)(C)C(C)(C)O3)[CH:49]=2)[CH2:43][CH2:42]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]>[CH2:31]([N:28]1[C:23]2=[N:24][C:25]([CH2:26][CH3:27])=[C:20]([CH2:19][N:10]([CH2:9][C:4]3[CH:3]=[C:2]([C:52]4[CH:51]=[CH:50][CH:49]=[C:48]([CH2:47][CH:44]5[CH2:45][CH2:46][N:41]([CH3:40])[CH2:42][CH2:43]5)[CH:53]=4)[C:7]([CH3:8])=[CH:6][CH:5]=3)[C:11]([C:13]3([C:16]([NH2:18])=[O:17])[CH2:15][CH2:14]3)=[O:12])[C:21]([NH:33][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[C:22]2[CH:30]=[N:29]1)[CH3:32]
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 69011639N1-[(3-bromo-4-methylphenyl)methyl]-N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,1-cyclopropanedicarboxamide

Product 1

HCID 69013870
N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N1-({6-methyl-3'-[(1-methyl-4-piperidinyl)methyl]-3-biphenylyl}methyl)-1,1-cyclopropanedicarboxamide
Yield 32.6%

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 N1-[(3-bromo-4-methylphenyl)methyl]-N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,1-cyclopropanedicarboxamide (35 mg, 0.059 mmol), 1-methyl-4-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}piperidine (23.51 mg, 0.059 mmol), Na2CO3 (18.62 mg, 0.176 mmol) and PdCl2(dppf) (4.29 mg, 5.86 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 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 was then washed with ethyl acetate and water. The organic layer was concentrated under vacuum to obtain the crude residue. It was purified by reverse phase hplc with a Gilson HPLC (acidic conditions: 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 washed with saturated NaHCO3 and 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 N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N1-({6-methyl-3′-[(1-methyl-4-piperidinyl)methyl]-3-biphenylyl}methyl)-1,1-cyclopropanedicarboxamide as a solid (13.5 mg, 32.6%). LC-MS m/z 707 (M+H)+, 0.76 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 water
  5. concentrationThe organic layer was concentrated under vacuum
  6. customto obtain the crude residue
  7. customIt was purified by reverse phase hplc with a Gilson HPLC (acidic conditions
  8. wash0.1% TFA in the solvents), eluting with 10 to 70% CH3CN in water at a flow rate of 20 mL/min
  9. washwashed with saturated NaHCO3
  10. extractionextracted with ethyl acetate twice
  11. washThe combined organic layers were washed with brine
  12. dry with materialdried over sodium sulfate
  13. filtrationfiltered
  14. concentrationconcentrated under vacuum

Sources & evidence

ORD record
ord-8541008851e4405dbfefb0d17adb895c
Source dataset
uspto-grants-2011_12
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08071588B2

Reaction notes

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