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

HRID 1520356Notes

Reaction equation

HRID 1520356 reaction equation
[Cl:1][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](I)[CH:8]=2)[N:3]=1.[CH3:22][N:23]([CH2:25][C:26]#[CH:27])[CH3:24].CCN(CC)CC>CN(C=O)C.O.C(OCC)(=O)C.[Cu]I.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>[Cl:1][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:27]#[C:26][CH2:25][N:23]([CH3:24])[CH3:22])[CH:8]=2)[N:3]=1

Participants

9

Reactant 3

HCID 8471TriethylamineHCID 81643N,N-DimethylpropargylamineHCID 866770782-chloro-N-(3-chloro-4-fluorophenyl)-6-iodoquinazolin-4-amine

Product 1

HCID 866770792-chloro-N-(3-chloro-4-fluorophenyl)-6-(3-(dimethylamino)prop-1-ynyl)quinazolin-4-amineYield 34.1%

Reagents, catalysts & solvents 5

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418476HCID 178418476, compoundCatalystHCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

In a 50 mL round-bottomed flask was added 2-chloro-N-(3-chloro-4-fluorophenyl)-6-iodoquinazolin-4-amine (200 mg, 0.46 mmol), N,N-dimethylpropargylamine (99 mL, 0.92 mmol), NEt3 (0.26 mL, 1.84 mmol), CuI (0.88 mg, 4.6 mmol) and PdCl2(PPh3)2 (6.5 mg, 9.2 mmol) in DMF (3 mL) to give a light yellow suspension. The mixture was stirred at room temperature overnight under an argon atmosphere. The reaction mixture was diluted with water (10 mL) and ethyl acetate (10 mL) and then a precipitate formed. The resulting precipitate was removed by filtration through Celite. The filtrate was extracted with ethyl acetate (2×10 mL). The combined organic layer was washed with water (1×15 mL) and brine (1×15 mL) and was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluted with CH2Cl2/MeOH 1:0 to 9:1). The desired product was washed with CH2Cl2 to give 61 mg of 2-chloro-N-(3-chloro-4-fluorophenyl)-6-(3-(dimethylamino)prop-1-ynyl)quinazolin-4-amine, as pale yellow solid in a 34% yield. LCMS m/z=389 (M+1) (Method C) (retention time=2.2.4 min). 1H NMR (300 MHz, DMSO) δ 10.30 (s, 1H), 8.68 (s, 1H), 8.07 (dd, J=2.7, 6.9 Hz, 1H), 7.86 (dd, J=1.8, 8.7 Hz, 1H), 7.81-7.70 (m, 1H), 7.68 (d, J=8.4 Hz, 1H), 7.49 (t, J=9.2 Hz, 1H), 3.52 (s, 2H), 2.28 (s, 6H).

Workup

  1. customto give a light yellow suspension
  2. customa precipitate formed
  3. customThe resulting precipitate was removed by filtration through Celite
  4. extractionThe filtrate was extracted with ethyl acetate (2×10 mL)
  5. washThe combined organic layer was washed with water (1×15 mL) and brine (1×15 mL)
  6. dry with materialwas dried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe residue was purified by column chromatography on silica gel (eluted with CH2Cl2/MeOH 1:0 to 9:1)
  10. washThe desired product was washed with CH2Cl2

Sources & evidence

ORD record
ord-6376e97fbbf749e1a949839101a84c49
Source dataset
uspto-grants-2015_07
Patent number
US09073890B2

Reaction notes

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