Lithium Hydroxide → 5-tert-Butyl-2-(3-(5-(1,5-dimethyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(hydroxymethyl)phenyl)isoindolin-1-one

HRID 1772095Notes

Reaction equation

HRID 1772095 reaction equation
C([O:4][CH2:5][C:6]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:27]=2)[C:22]1=[O:34])(=O)C.Br[C:36]1[CH:37]=[C:38]([NH:44][C:45]2[CH:49]=[C:48]([CH3:50])[N:47]([CH3:51])[N:46]=2)[C:39](=[O:43])[N:40]([CH3:42])[CH:41]=1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Li+]>[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.O.C(O)C.C1COCC1.O1CCOCC1>[C:30]([C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[C:22](=[O:34])[N:21]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:36]3[CH:37]=[C:38]([NH:44][C:45]4[CH:49]=[C:48]([CH3:50])[N:47]([CH3:51])[N:46]=4)[C:39](=[O:43])[N:40]([CH3:42])[CH:41]=3)[C:6]=1[CH2:5][OH:4])[CH2:29]2)([CH3:32])([CH3:33])[CH3:31]

Participants

10

Reactant 4

HCID 3939Lithium HydroxideHCID 10340Sodium CarbonateHCID 666135055-Bromo-3-(1,5-dimethyl-1H-pyrazol-3-ylamino)-1-methylpyridin-2(1H)-oneHCID 866979362-(5-tert-Butyl-1-oxoisoindolin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl Acetate

Product 1

HCID 569284435-tert-Butyl-2-(3-(5-(1,5-dimethyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(hydroxymethyl)phenyl)isoindolin-1-one

Reagents, catalysts & solvents 5

HCID 11979704Tetrakis(triphenylphosphine)palladiumCatalystHCID 702EthanolSolventHCID 962WaterSolvent2×HCID 8028TetrahydrofuranSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A 100-mL three-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 103f (556 mg, 1.20 mmol), 105a (300 mg, 1.00 mmol), sodium carbonate (424 mg, 4.00 mmol), water (4 mL) and 1,4-dioxane (20 mL). After bubbling nitrogen through the resulting suspension for 20 min, tetrakis(triphenylphosphine)-palladium(0) (115 mg, 0.100 mmol) was added, and the reaction mixture was heated at 100° C. for 4 h. After this time, the reaction mixture was cooled to room temperature and filtered, and the filter cake was washed with a 1:10 mixture of methanol and methylene chloride (30 mL). The filtrate was concentrated under reduced pressure to afford a brown residue. Another 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with residue obtained above, THF (5 mL), ethanol (5 mL), water (5 mL) and lithium hydroxide (86.4 mg, 3.60 mmol). The mixture was stirred at 50° C. for 2 h. After this time, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by flash chromatography to afford a 35% (190 mg) yield of 105 as a white solid: mp 225-227° C.; 1H NMR (500 MHz, DMSO-d6) δ 7.94 (s, 2H), 7.72 (d, 1H, J=7.5 Hz), 7.71 (s, 1H), 7.61 (d, 1H, J=7.5 Hz), 7.48 (t, 1H, J=7.5 Hz), 7.42 (d, 1H, J=7.5 Hz), 7.36 (d, 1H, J=7.5 Hz), 7.22 (s, 1H), 5.88 (s, 1H), 4.89 (s, 2H), 4.88 (t, 1H, J=4.5 Hz), 4.35 (d, 2H, J=4.5 Hz), 3.57 (s, 3H), 3.56 (s, 3H), 2.17 (s, 3H), 1.36 (s, 9H); MS (ESI+) m/z 512.3 (M+H).

Workup

  1. customA 100-mL three-neck round-bottomed flask equipped with a magnetic stirrer
  2. temperaturereflux condenser
  3. customAfter bubbling nitrogen through the resulting suspension for 20 min
  4. temperatureAfter this time, the reaction mixture was cooled to room temperature
  5. filtrationfiltered
  6. washthe filter cake was washed with a 1:10 mixture of methanol and methylene chloride (30 mL)
  7. concentrationThe filtrate was concentrated under reduced pressure
  8. customto afford a brown residue
  9. customAnother 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer
  10. temperaturereflux condenser
  11. additionwas charged with residue
  12. customobtained above
  13. concentrationAfter this time, the reaction mixture was concentrated under reduced pressure
  14. customThe resulting residue was purified by flash chromatography

Sources & evidence

ORD record
ord-0fee79c26d174a6d8ca18ad912852ed7
Source dataset
uspto-grants-2016_02
Patent number
US09249123B2

Reaction notes

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