Cesium carbonate → Tert-butyl 5-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-4-methylpyridin-2-ylcarbamate

HRID 468842Notes

Reaction equation

HRID 468842 reaction equation
Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)=[C:4]([CH3:24])[CH:3]=1.[C:25](=[O:32])([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[NH2:26].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.[Cl-].[Na+].O>[CH:21]1([C:19]([NH:18][C:13]2[N:14]=[CH:15][C:16]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[C:8]([C:5]2[C:4]([CH3:24])=[CH:3][C:2]([NH:26][C:25](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[N:7][CH:6]=2)[CH:17]=3)=[O:20])[CH2:23][CH2:22]1

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 77922tert-Butyl carbamate2×HCID 76401541N-(7-(6-chloro-4-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide

Product 1

HCID 67977233Tert-butyl 5-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-4-methylpyridin-2-ylcarbamate

Reagents, catalysts & solvents 2

HCID 312751,4-DioxaneSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
90 °C

Procedure

A mixture of N-(7-(6-chloro-4-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide (63.5 mg, 188 μmol), tert-butyl carbamate (46.7 mg, 399 μmol), chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-1,1′-biphenyl][2-(2-aminoeth yl)phenyl]palladium(II) (16.9 mg, 21 μmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-1,1′-biphenyl (10.6 mg, 20 μmol), and cesium carbonate (127 mg, 390 μmol) in 1,4-dioxane (1.0 mL) was heated in a sealed vessel at 90° C. for 20 hours. The mixture was treated with further portions of tert-butyl carbamate (67.1 mg, 537 μmol), chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-1,1′-biphenyl][2-(2-aminoeth yl)phenyl]palladium(II) (20.1 mg, 25 μmol) and 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-1,1′-biphenyl (12.9 mg, 24 μmol) and heated at 90° C. for a further 24 hours. The cooled mixture was diluted with brine, extracted twice into dichloromethane, and twice more with DCM to which methanol was added. The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in DCM, filtered through a celite pad and concentrated in vacuo to afford the impure title compound as a brown solid, used in the next step without purification. LCMS: M+H+=419.

Workup

  1. temperatureheated at 90° C. for a further 24 hours
  2. extractionextracted twice into dichloromethane
  3. additiontwice more with DCM to which methanol was added
  4. dry with materialThe combined organic phases were dried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. dissolutionThe residue was dissolved in DCM
  8. filtrationfiltered through a celite pad
  9. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-4a2a49f87736428eb80ea30b286c55e3
Source dataset
uspto-grants-2014_01
Patent number
US08623889B2

Reaction notes

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