Potassium Carbonate → N-(4-bromo-2-fluorophenyl)-7-methoxy-6-(3-(tetrahydro-2H-[1,4]dioxino[2,3-c]pyrrol-6(3H)-yl)propoxy)quinazolin-4-amine

HRID 712415Notes

Reaction equation

HRID 712415 reaction equation
Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH:8]2[O:10][CH2:11][CH2:12][O:13][CH:7]2[CH2:6]1.[F:14][C:15]1[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:16]=1[NH:22][C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:34][CH3:35])=[C:30]([OH:33])[CH:31]=2)[N:26]=[CH:25][N:24]=1.C([O-])([O-])=O.[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[Br:21][C:19]1[CH:18]=[CH:17][C:16]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][C:29]([O:34][CH3:35])=[C:30]([O:33][CH2:2][CH2:3][CH2:4][N:5]4[CH2:9][CH:8]5[O:10][CH2:11][CH2:12][O:13][CH:7]5[CH2:6]4)[CH:31]=3)[N:26]=[CH:25][N:24]=2)=[C:15]([F:14])[CH:20]=1

Participants

6

Reactant 3

HCID 11430Potassium CarbonateHCID 210983904-((4-Bromo-2-fluorophenyl)amino)-7-methoxyquinazolin-6-olHCID 867294746-(3-chloropropyl)hexahydro-2H-[1,4]dioxino[2,3-c]pyrrole

Product 1

HCID 71573031N-(4-bromo-2-fluorophenyl)-7-methoxy-6-(3-(tetrahydro-2H-[1,4]dioxino[2,3-c]pyrrol-6(3H)-yl)propoxy)quinazolin-4-amineYield 54.2%

Reagents, catalysts & solvents 2

HCID 67553Tetrabutylammonium IodideCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

A mixture of 6-(3-chloropropyl)hexahydro-2H-[1,4]dioxino[2,3-c]pyrrole (0.58 g, 2.82 mmol, 1.2 eq), 4-((2-fluoro-4-bromophenyl)amino)-7-methoxyquinazolin-6-ol (0.49 g, 1.35 mmol, 1.0 eq), anhydrous K2CO3 (0.56 g, 4.05 mmol, 3.0 eq) and tetrabutylammonium iodide (25 mg, 0.06 mmol, 0.05 eq) in DMF (8 mL) was heated at 80° C. for 11 h. The reaction mixture was cooled to room temperature and quenched with water (10 mL). The resulted mixture was diluted with EtOAc (20 mL) and the organic phase was separated from the mixture. The water phase was extracted with EtOAc (20 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (20:1 (v/v) CH2Cl2/CH3OH) to give the crude product, which was recrystallized from CH2Cl2/PE to afford the title compound as a pale yellow solid (0.39 g, 54.00%), HPLC: 96.20%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 535.1 (M+1); 1H NMR (400 MHz, CDCl3) δ: 2.13 (2H, m), 2.77 (2H, t, J=7.2 Hz), 2.84 (2H, dd, J=6.4, 10.4 Hz), 2.95 (2H, dd, J=4.0, 10.4 Hz), 3.56 (2H, m), 3.80 (2H, m), 4.02 (3H, s), 4.10 (2H, m), 4.25 (2H, t, J=6.4 Hz), 7.13 (1H, s), 7.26-7.37 (3H, m), 8.38 (1H, t, J=8.4 Hz), 8.67 (1H, s) ppm.

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. customquenched with water (10 mL)
  3. additionThe resulted mixture was diluted with EtOAc (20 mL)
  4. customthe organic phase was separated from the mixture
  5. extractionThe water phase was extracted with EtOAc (20 mL×3)
  6. dry with materialThe combined organic phases were dried over anhydrous Na2SO4
  7. filtrationfiltered
  8. concentrationThe filtrate was concentrated in vacuo
  9. customthe residue was purified by a silica gel column chromatography (20:1 (v/v) CH2Cl2/CH3OH)
  10. customto give the crude product, which
  11. customwas recrystallized from CH2Cl2/PE

Sources & evidence

ORD record
ord-5c84fe0ddaa043f48396d909592b7b7b
Source dataset
uspto-grants-2015_11
Patent number
US09181277B2

Reaction notes

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