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]propanediamide

HRID 657295Notes

Reaction equation

HRID 657295 reaction equation
Br[C:2]1[CH:3]=[C:4]([CH2:9][NH:10][C:11](=[O:37])[CH2:12][C:13]([NH:15][CH2:16][C:17]2[C:18]([NH:30][CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[C:19]3[CH:27]=[N:26][N:25]([CH2:28][CH3:29])[C:20]3=[N:21][C:22]=2[CH2:23][CH3:24])=[O:14])[CH:5]=[CH:6][C:7]=1[F:8].[CH:38]([C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1)=[O:39].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:28]([N:25]1[C:20]2=[N:21][C:22]([CH2:23][CH3:24])=[C:17]([CH2:16][NH:15][C:13](=[O:14])[CH2:12][C:11]([NH:10][CH2:9][C:4]3[CH:3]=[C:2]([C:44]4[CH:43]=[CH:42][CH:41]=[C:40]([CH:38]=[O:39])[CH:45]=4)[C:7]([F:8])=[CH:6][CH:5]=3)=[O:37])[C:18]([NH:30][CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[C:19]2[CH:27]=[N:26]1)[CH3:29]

Participants

7

Reactant 3

HCID 10340Sodium CarbonateHCID 27343563-Formylphenylboronic acidHCID 57819933N-[(3-bromo-4-fluorophenyl)methyl]-N'-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}propanediamide

Product 1

HCID 57819896N-{[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]propanediamideYield 66.1%

Reagents, catalysts & solvents 3

HCID 11979704Tetrakis(triphenylphosphine)palladiumCatalystHCID 962WaterSolvent2×HCID 312751,4-DioxaneSolvent

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}propanediamide (0.9429 g, 1.638 mmol), (3-formylphenyl)boronic acid (0.300 g, 2.0 mmol), tetrakis (triphenylphosphine) palladium (0) (0.092 g, 0.08 mmol), sodium carbonate (0.530 g, 5.0 mmol), in 1,4-dioxane (12 mL) and water (4 mL) was microwaved for 30 min at 140° C.; however, the reaction failed and appeared to be incomplete by color. The mixture was again microwaved at 150° C. for about two min. The LC-MS showed that the reaction was complete. The reaction mixture was diluted with water, extracted with EtOAc twice. The organic extracts were filtered through a glass-fibre filter and washed with saturated NaCl, then dried over Na2SO4. The organic layer was evaporated to dryness and taken up in a small amount of DCM, introduced onto a Chromatotron Plate (silica gel −2,000μ) and eluted with DCM-MeOH (2-7%). The product fractions were dried 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]propanediamide (650 mg, 62.7%) as a glassy solid. LC-MS m/z 601.4 (M+H)+, 0.83 min (ret time).

Workup

  1. customThe mixture was again microwaved at 150° C. for about two min
  2. extractionextracted with EtOAc twice
  3. filtrationThe organic extracts were filtered through a glass-fibre filter
  4. washwashed with saturated NaCl
  5. dry with materialdried over Na2SO4
  6. customThe organic layer was evaporated to dryness
  7. additionintroduced onto a Chromatotron Plate (silica gel −2,000μ)
  8. washeluted with DCM-MeOH (2-7%)
  9. customThe product fractions were dried

Sources & evidence

ORD record
ord-4e8990a8822646abbeef005ba69b5eec
Source dataset
uspto-grants-2011_12
Patent number
US08071588B2

Reaction notes

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