Lithium Hydroxide → 6-(Dimethylamino)-2-[2-(Hydroxymethyl)-3-(1-Methyl-5-{[5-(Morpholin-4-Ylcarbonyl)pyridin-2-Yl]amino}-6-Oxo-1,6-Dihydropyridin-3-Yl)phenyl]-3,4-Dihydroisoquinolin-1(2h)-One

HRID 2245659Notes

Reaction equation

HRID 2245659 reaction equation
[CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])=[CH:20][N:19]=2)[C:3]1=[O:32].Br[C:34]1[CH:44]=[CH:43][CH:42]=[C:41]([N:45]2[CH2:54][CH2:53][C:52]3[C:47](=[CH:48][CH:49]=[C:50]([N:55]([CH3:57])[CH3:56])[CH:51]=3)[C:46]2=[O:58])[C:35]=1[CH2:36][O:37]C(=O)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[OH-].[Li+]>>[CH3:56][N:55]([CH3:57])[C:50]1[CH:51]=[C:52]2[C:47](=[CH:48][CH:49]=1)[C:46](=[O:58])[N:45]([C:41]1[CH:42]=[CH:43][CH:44]=[C:34]([C:6]3[CH:5]=[C:4]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([C:24]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[O:25])=[CH:20][N:19]=4)[C:3](=[O:32])[N:2]([CH3:1])[CH:7]=3)[C:35]=1[CH2:36][OH:37])[CH2:54][CH2:53]2

Participants

5

Reactant 4

HCID 3939Lithium HydroxideHCID 62657Potassium Phosphate, TribasicHCID 59216405Acetic acid 2-bromo-6-(6-dimethylamino-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-benzyl esterHCID 592164661-Methyl-3-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one

Product 1

HCID 441552526-(Dimethylamino)-2-[2-(Hydroxymethyl)-3-(1-Methyl-5-{[5-(Morpholin-4-Ylcarbonyl)pyridin-2-Yl]amino}-6-Oxo-1,6-Dihydropyridin-3-Yl)phenyl]-3,4-Dihydroisoquinolin-1(2h)-OneYield 59%

Conditions

Temperature
100 °C

Procedure

To 1-Methyl-3-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one (60 mg, 0.14 mmol), Acetic acid 2-bromo-6-(6-dimethylamino-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-benzyl ester (46 mg, 0.1 mmol), potassium phosphate (47 mg, 0.22 mmol), 2-(dicyclohexylphoshphino)-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (3.1 mg, 0.0065 mmol), and bis(dibenzylidineacetone)palladium(0) (1.9 mg, 0033 mmol) was added 4 mL of degassed 1:3 water/n-butanol. The headspace of the vessel was evacuated and backfilled with argon 4 times. This was heated at 100° C. for 110 minutes. This was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. This was dissolved in 2 mL tetrahydrofuran, 1 mL methanol, and 1 mL water. 1M aq. lithium hydroxide solution (0.33 mL, 0.33 mmol) was added. After stirring for 18 hours, the resulting mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (gradient elution 2 to 5% methanol/dichloromethane) to yield 6-Dimethylamino-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one (36 mg, 0.059 mmol). MS (ESI) 609.1 (M+H)+.

Workup

  1. customof degassed 1:3 water/n-butanol
  2. customThe headspace of the vessel was evacuated
  3. customThis was partitioned between ethyl acetate and water
  4. washThe ethyl acetate layer was washed with brine
  5. dry with materialdried over anhydrous magnesium sulfate
  6. concentrationconcentrated in vacuo
  7. dissolutionThis was dissolved in 2 mL tetrahydrofuran
  8. customthe resulting mixture was partitioned between ethyl acetate and water
  9. washThe ethyl acetate layer was washed with brine
  10. dry with materialdried over anhydrous magnesium sulfate
  11. concentrationconcentrated in vacuo
  12. custompurified by flash chromatography (gradient elution 2 to 5% methanol/dichloromethane)

Sources & evidence

ORD record
ord-af16b2e5de604acfb00531fc49369d22
Source dataset
uspto-grants-2010_03
Patent number
US07683064B2

Reaction notes

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