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

HRID 564637Notes

Reaction equation

HRID 564637 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])[CH:14]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].CC1(C)C(C)(C)OB([C:51]2[CH:52]=[C:53]([CH2:57][CH:58]3[CH2:63][CH2:62][N:61](C(OC(C)(C)C)=O)[CH2:60][CH2:59]3)[CH:54]=[CH:55][CH:56]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[CH2:34]([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:55]5[CH:56]=[CH:51][CH:52]=[C:53]([CH2:57][CH:58]6[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]6)[CH:54]=5)[C:7]([F:8])=[CH:6][CH:5]=4)=[O:12])[CH: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 11430Potassium CarbonateHCID 57813256N-[(3-Bromo-4-fluorophenyl)methyl]-N'-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamideHCID 578134461,1-Dimethylethyl 4-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-1-piperidinecarboxylate

Product 1

HCID 44181204N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N'-{[6-fluoro-3'-(4-piperidinylmethyl)-3-biphenylyl]methyl}-1,3-benzenedicarboxamideYield 39%

Reagents, catalysts & solvents 3

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

Conditions

Temperature
130 °C

Procedure

To a solution 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}-1,3-benzenedicarboxamide (0.166 g, 0.26 mmol) in 1,4-dioxane (3 mL) and H2O (1 mL) was added 1,1-dimethylethyl 4-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-1-piperidinecarboxylate (0.157 g, 0.390 mmol), Pd(Ph3P)4 (0.015 g, 0.013 mmol), and K2CO3 (0.144 g, 1.040 mmol). This mixture was heated in a microwave at 130° C. for 15 min. The organic layer was separated, filtered, concentrated, and purified with a Gilson HPLC (with 0.1% TFA). Before the sample was concentrated with GeneVav EZ-2, TFA (5 drops) was added to each tube (12 mL). The resultant mixture was concentrated, purified with a Gilson HPLC (with 0.1% TFA), concentrated, and basified with an amino cartridge to afford 0.0738 g (39%) of the title compound. LC-MS m/z 732 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 1.36-1.52 (m, 8 H) 1.81-1.93 (m, 4 H) 2.09 (d, J=11.54 Hz, 2 H) 2.62-2.70 (m, 2 H) 2.87-2.98 (m, 2 H) 3.16 (q, 2 H) 3.19-3.30 (m, 1 H) 3.32-3.39 (m, J=12.55 Hz, 2 H) 3.62-3.71 (m, 2 H) 3.99-4.07 (m, 2 H) 4.29-4.40 (m, J=4.27, 4.27 Hz, 1 H) 4.48 (q, J=7.11 Hz, 2 H) 4.60 (s, 2 H) 4.68-4.75 (m, 2 H) 7.14 (dd, J=10.54, 8.53 Hz, 1 H) 7.18-7.26 (m, 1 H) 7.33-7.44 (m, 4 H) 7.44-7.50 (m, J=7.53, 2.26 Hz, 1 H) 7.59 (t, J=7.78 Hz, 1 H) 8.01-8.08 (m, 2 H) 8.28 (s, 1 H) 8.39 (s, 1 H).

Workup

  1. customThe organic layer was separated
  2. filtrationfiltered
  3. concentrationconcentrated
  4. custompurified with a Gilson HPLC (with 0.1% TFA)
  5. concentrationBefore the sample was concentrated with GeneVav EZ-2, TFA (5 drops)
  6. additionwas added to each tube (12 mL)
  7. concentrationThe resultant mixture was concentrated
  8. custompurified with a Gilson HPLC (with 0.1% TFA)
  9. concentrationconcentrated

Sources & evidence

ORD record
ord-dca4d3c4b5814eb5ab722e860798ec92
Source dataset
uspto-grants-2011_11
Patent number
US08067408B2

Reaction notes

Loading…