Dichloromethane → N-(4-bromo-2-fluorophenyl)-6-(3-(hexahydrofuro[3,4-c]pyridin-5(3H)-yl)propoxy)-7-methoxyquinazolin-4-amine

HRID 712526Notes

Reaction equation

HRID 712526 reaction equation
[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([OH:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[C:4]([F:22])[CH:3]=1.Cl[CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH:30]2[CH2:33][O:34][CH2:35][CH:29]2[CH2:28]1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([O:19][CH2:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][CH:30]5[CH2:33][O:34][CH2:35][CH:29]5[CH2:28]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[C:4]([F:22])[CH:3]=1

Participants

6

Reactant 4

HCID 6344DichloromethaneHCID 11430Potassium CarbonateHCID 210983904-((4-Bromo-2-fluorophenyl)amino)-7-methoxyquinazolin-6-olHCID 867295055-(3-Chloropropyl)octahydrofuro[3,4-c]pyridine

Product 1

HCID 86729524N-(4-bromo-2-fluorophenyl)-6-(3-(hexahydrofuro[3,4-c]pyridin-5(3H)-yl)propoxy)-7-methoxyquinazolin-4-amineYield 60.5%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

A mixture of 4-((4-bromo-2-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (225 mg, 0.62 mmol, 1 eq), 5-(3-chloropropyl)octahydrofuro[3,4-c]pyridine (151 mg, 0.74 mmol, 1.2 eq) and K2CO3 (171 mg, 1.24 mmol, 2 eq) in DMF (10 mL) was stirred at 80° C. overnight and cooled to room temperature. To this, CH2Cl2 (50 mL) was added. The mixture was washed with brine (20 mL×3) and water (20 mL×2), then dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (eluting agent: 20:1 (v/v) CH2Cl2/CH3OH) to give the title compound as a yellow solid (199 mg, 60.50%), HPLC: 98.32%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 531.1 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.69-1.73 (2H, m), 2.41-2.46 (3H, m), 2.64-2.66 (2H, m), 2.68-2.70 (3H, m), 2.75-2.82 (2H, m), 3.00-3.03 (3H, m), 3.06-3.10 (2H, m), 3.81-3.85 (2H, m), 4.23-4.27 (2H, m), 7.06-7.12 (1H, m), 7.21 (1H, s), 7.68-7.79 (2H, m), 7.87 (1H, s), 8.06-8.11 (1H, m), 8.65 (1H, s) ppm.

Workup

  1. temperaturecooled to room temperature
  2. washThe mixture was washed with brine (20 mL×3) and water (20 mL×2)
  3. dry with materialdried over anhydrous Na2SO4
  4. filtrationfiltered
  5. concentrationThe filtrate was concentrated in vacuo
  6. customthe residue was purified by a silica gel column chromatography (eluting agent: 20:1 (v/v) CH2Cl2/CH3OH)

Sources & evidence

ORD record
ord-9761dc966d3b4d52b63c7ca1af7c2455
Source dataset
uspto-grants-2015_11
Patent number
US09181277B2

Reaction notes

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