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

HRID 712520Notes

Reaction equation

HRID 712520 reaction equation
[C:1]([C:3]1[CH:4]=[C:5]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:22][CH3:23])=[C:18]([OH:21])[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[F:9])#[CH:2].Cl[CH2:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][CH:31]2[CH2:34][O:35][CH2:36][CH:30]2[CH2:29]1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:22][CH3:23])=[C:18]([O:21][CH2:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][CH:31]5[CH2:34][O:35][CH2:36][CH:30]5[CH2:29]4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[F:9])#[CH:2]

Participants

6

Reactant 4

HCID 6344DichloromethaneHCID 11430Potassium CarbonateHCID 451405424-((3-Ethynyl-4-fluorophenyl)amino)-7-methoxyquinazolin-6-olHCID 867295055-(3-Chloropropyl)octahydrofuro[3,4-c]pyridine

Product 1

HCID 71572917N-(3-ethynyl-4-fluorophenyl)-6-(3-(hexahydrofuro[3,4-c]pyridin-5(3H)-yl)propoxy)-7-methoxyquinazolin-4-amineYield 52.5%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

A mixture of 4-((3-ethynyl-4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (220 mg, 0.71 mmol, 1 eq), 5-(3-chloropropyl)octahydrofuro[3,4-c]pyridine (174 mg, 0.44 mmol, 1.2 eq) and K2CO3 (197 mg, 1.42 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 (110 mg, 32.50%), HPLC: 97.45%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 477.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.76-1.77 (2H, m), 2.24-2.48 (3H, m), 2.50-2.64 (2H, m), 2.68-2.71 (3H, m), 2.73-2.75 (2H, m), 2.96-3.03 (3H, m), 3.07-3.12 (2H, m), 3.61-3.90 (2H, m), 4.07 (1H, s), 4.24-4.27 (2H, m), 7.06-7.10 (1H, m), 7.16 (1H, s), 7.76-7.82 (1H, m), 7.82 (1H, s), 8.09-8.11 (1H, m), 8.59 (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-aded5cc1d0bf4711baf869b1f3e20614
Source dataset
uspto-grants-2015_11
Patent number
US09181277B2

Reaction notes

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