Water → N-(3-chloro-4-fluorophenyl)-6-(3-(dimethylamino)prop-1-ynyl)-2-(pyridin-3-yl)quinazolin-4-amine

HRID 1520357Notes

Reaction equation

HRID 1520357 reaction equation
Cl[C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:21]#[C:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH:8]=2)[N:3]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[Cl:20][C:15]1[CH:14]=[C:13]([NH:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:21]#[C:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH:8]=3)[N:3]=[C:2]([C:29]3[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=3)[N:11]=2)[CH:18]=[CH:17][C:16]=1[F:19]

Participants

8

Reactant 4

HCID 962WaterHCID 11430Potassium CarbonateHCID 27343783-Pyridinylboronic acidHCID 866770792-chloro-N-(3-chloro-4-fluorophenyl)-6-(3-(dimethylamino)prop-1-ynyl)quinazolin-4-amine

Product 1

HCID 67298134N-(3-chloro-4-fluorophenyl)-6-(3-(dimethylamino)prop-1-ynyl)-2-(pyridin-3-yl)quinazolin-4-amineYield 37%

Reagents, catalysts & solvents 3

HCID 178418476HCID 178418476, compoundCatalystHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Procedure

In a 50 mL round-bottomed flask was added 2-chloro-N-(3-chloro-4-fluorophenyl)-6-(3-(dimethylamino)prop-1-ynyl)quinazolin-4-amine, (61 mg, 0.16 mmol), 3-pyridineboronic acid (25 mg, 0.20 mmol), K2CO3 (0.11 mg, 0.78 mmol) and PdCl2(PPh3)2, (5.5 mg, 7.8 mM) in dioxane (2 mL) to give a yellow suspension. The mixture was heated at reflux for 3 h under argon. After cooling to room temperature, water (10 mL) and ethyl acetate (10 mL) were added to the mixture to form a precipitate. The resulting precipitate was filtered through Celite. The filtrate was extracted with ethyl acetate (2×10 mL) and the combined organic layers were washed with water (1×15 mL) and brine (1×15 mL) and then dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluted with AcOEt/MeOH 1:0 to 9:1). The desired product was washed with CH2Cl2 to give 25 mg of N-(3-chloro-4-fluorophenyl)-6-(3-(dimethylamino)prop-1-ynyl)-2-(pyridin-3-yl)quinazolin-4-amine as a light brown solid in 37% yield. LCMS m/z=432 (M+1) (Method C) (retention time=1.86 ruin). 1H NMR (300 MHz, DMSO) δ 10.13 (s, 1H), 9.51 (s, 1H), 8.77-8.56 (m, 3H), 8.26 (dd, J=6.9, 2.5 Hz, 1H), 8.02-7.78 (m, 3H), 7.64-7.47 (m, 2H), 3.54 (s, 2H), 2.30 (s, 6H).

Workup

  1. customto give a yellow suspension
  2. temperatureThe mixture was heated
  3. temperatureat reflux for 3 h under argon
  4. customto form a precipitate
  5. filtrationThe resulting precipitate was filtered through Celite
  6. extractionThe filtrate was extracted with ethyl acetate (2×10 mL)
  7. washthe combined organic layers were washed with water (1×15 mL) and brine (1×15 mL)
  8. dry with materialdried over Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customThe residue was purified by column chromatography on silica gel (eluted with AcOEt/MeOH 1:0 to 9:1)
  12. washThe desired product was washed with CH2Cl2

Sources & evidence

ORD record
ord-14bc31764a9d4320ac3d18ef71731919
Source dataset
uspto-grants-2015_07
Patent number
US09073890B2

Reaction notes

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