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

HRID 712399Notes

Reaction equation

HRID 712399 reaction equation
[O:1]1[CH:6]2[CH2:7][NH:8][CH2:9][CH:5]2[O:4][CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:34][CH3:35])=[C:26]([O:29][CH2:30][CH2:31][CH2:32]Cl)[CH:27]=3)[N:22]=[CH:21][N:20]=2)[CH:14]=[CH:15][C:16]=1[F:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:34][CH3:35])=[C:26]([O:29][CH2:30][CH2:31][CH2:32][N:8]4[CH2:7][CH:6]5[O:1][CH2:2][CH2:3][O:4][CH:5]5[CH2:9]4)[CH:27]=3)[N:22]=[CH:21][N:20]=2)[CH:14]=[CH:15][C:16]=1[F:17]

Participants

5

Reactant 3

HCID 11430Potassium CarbonateHCID 50742265N-(3-Chloro-4-fluorophenyl)-6-(3-chloropropoxy)-7-methoxyquinazolin-4-amineHCID 82418726hexahydro-2H-[1,4]dioxino[2,3-c]pyrrole

Product 1

HCID 71573379N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-(tetrahydro-2H-[1,4]dioxino[2,3-c]pyrrol-6(3H)-yl)propoxy)quinazolin-4-amineYield 25%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
60 °C

Procedure

A mixture of hexahydro-2H-[1,4]dioxino[2,3-c]pyrrole (1.0 eq), N-(3-chloro-4-fluorophenyl)-6-(3-chloropropoxy)-7-methoxyquinazolin-4-amine (710 mg, 1.8 mmol, 0.95 eq), K2CO3 (524 mg, 3.8 mmol, 2.0 eq) and KI (16 mg, 0.095 mmol, 0.05 eq) in DMF (12 mL) was heated at 60° C. for 3 h and cooled to room temperature. The reaction mixture was quenched with water (10 mL) and diluted with EtOAc (20 mL). The organic phase was separated from the mixture, and the water phase was extracted with EtOAc (20 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. 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 grayish-white solid (230 mg, 25.00%), HPLC: 99.11%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 489.9 (M+1); 1H NMR (400 MHz, CDCl3) δ: 2.09 (2H, m), 2.74 (4H, m), 2.99 (2H, dd, J=3.3, 10.4 Hz), 3.56 (2H, m), 3.80 (2H, m), 3.99 (3H, s), 4.12 (2H, t, J=3.5 Hz), 4.22 (2H, t, J=6.8 Hz), 7.14 (1H, t, J=8.8 Hz), 7.23 (1H, s), 7.29 (1H, d, J=15.8 Hz), 7.60 (1H, m), 7.89 (1H, dd, J=2.5, 6.5 Hz), 8.63 (1H, s) ppm.

Workup

  1. temperaturecooled to room temperature
  2. customThe reaction mixture was quenched with water (10 mL)
  3. additiondiluted 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. concentrationconcentrated in vacuo
  8. customThe residue was purified by a silica gel column chromatography (20:1 (v/v) CH2Cl2/CH3OH)
  9. customto give the crude product, which
  10. customwas recrystallized from CH2Cl2/PE

Sources & evidence

ORD record
ord-9697efb05b964ac289c5e36a654633c4
Source dataset
uspto-grants-2015_11
Patent number
US09181277B2

Reaction notes

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