Cesium carbonate → N4-(2,2-dimethyl-3,4-dihydro-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-5-fluoro-N2-(isoquinolin-7-yl)-2,4-pyrimidinediamine

HRID 1916047Notes

Reaction equation

HRID 1916047 reaction equation
Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[O:13][C:14]([CH3:21])([CH3:20])[C:15](=[O:19])[NH:16][C:17]=3[N:18]=2)[C:5]([F:22])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:33]=[C:32]2[C:27]([CH:28]=[CH:29][N:30]=[CH:31]2)=[CH:26][CH:25]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.CN1C(=O)CCC1.C(Cl)Cl.CO.CC(C)=O.CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:20][C:14]1([CH3:21])[O:13][C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6]3[C:5]([F:22])=[CH:4][N:3]=[C:2]([NH:23][C:24]4[CH:33]=[C:32]5[C:27]([CH:28]=[CH:29][N:30]=[CH:31]5)=[CH:26][CH:25]=4)[N:7]=3)=[N:18][C:17]=2[NH:16][C:15]1=[O:19]

Participants

10

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 14660277Isoquinolin-7-amineHCID 575629316-((2-Chloro-5-fluoro-4-pyrimidinyl)amino)-2,2-dimethyl-2H-pyrido(3,2-b)-1,4-oxazin-3(4H)-one

Product 1

HCID 53477410N4-(2,2-dimethyl-3,4-dihydro-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-5-fluoro-N2-(isoquinolin-7-yl)-2,4-pyrimidinediamineYield 15.5%

Reagents, catalysts & solvents 5

HCID 167845palladium(II) acetateCatalystHCID 13387N-methyl-2-pyrrolidoneSolventHCID 312751,4-DioxaneSolventHCID 21226129Dichloromethane methanolSolventHCID 21894497Aceton-methanolSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 1.6 g 2-chloro-5-fluoro-N4-[2,2-dimethyl-3,4-dihydro-3-oxo-pyrido[3,2-b][1,4]oxazin-6-yl]-4-pyrimidineamine, 800 mg of 7-aminoisoquinoline, 320 mg of palladium acetate, 320 mg of rac-Binap and 3.68 g cesium carbonate in 32 mL of 1,4-dioxane and 8 mL of NMP was heated at reflux at 100° C. overnight under argon. The reaction was cooled, diluted with CH2Cl2/MeOH and filtered. The filtrate was diluted with water and the organic phase evaporated to give the crude product which was dissolved in acetone/MeOH and evaporated onto silica gel. The material was purified by flash chromatography eluting isocratically with CH2Cl2/2 N ammonia solution in MeOH 15:1 to yield 330 mg of the title compound. 1H NMR (DMSO-d6): δ 8.91 (s, 1H), 8.48 (s, 1H), 8.28 (d, 1H), J=5.4 Hz), 8.16 (d, 1H, J=2.1 Hz), 7.82 (m, 2H), 7.68 (d, 1H, J=6 Hz), 7.51 (d, 1H, J=8.1 Hz), 7.30 (d, 1H, J=8.4 Hz), 1.43 (s, 6H); LCMS: purity: 99%; MS (m/e): 432 (MH+)

Workup

  1. temperaturewas heated
  2. temperatureThe reaction was cooled
  3. filtrationfiltered
  4. additionThe filtrate was diluted with water
  5. customthe organic phase evaporated
  6. customto give the crude product which
  7. customevaporated onto silica gel
  8. customThe material was purified by flash chromatography
  9. washeluting isocratically with CH2Cl2/2 N ammonia solution in MeOH 15:1

Sources & evidence

ORD record
ord-f56aea9faf844889a5042e37635c5de8
Source dataset
uspto-grants-2013_12
Patent number
US08618095B2

Reaction notes

Loading…