Dichloromethane → 2-(3-((4-((4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)propyl)hexahydropyrano[3,4-c]pyrrol-4(2H)-one

HRID 712527Notes

Reaction equation

HRID 712527 reaction equation
Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH:8]2[CH2:10][CH2:11][O:12][C:13](=[O:14])[CH:7]2[CH2:6]1.C([O-])([O-])=O.[K+].[K+].[F:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]2[C:38]3[C:33](=[CH:34][C:35]([O:40][CH3:41])=[C:36]([OH:39])[CH:37]=3)[N:32]=[CH:31][N:30]=2)=[CH:24][CH:23]=1.C(Cl)Cl>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:21][C:22]1[CH:23]=[CH:24][C:25]([NH:28][C:29]2[C:38]3[C:33](=[CH:34][C:35]([O:40][CH3:41])=[C:36]([O:39][CH2:2][CH2:3][CH2:4][N:5]4[CH2:9][CH:8]5[CH2:10][CH2:11][O:12][C:13](=[O:14])[CH:7]5[CH2:6]4)[CH:37]=3)[N:32]=[CH:31][N:30]=2)=[CH:26][CH:27]=1

Participants

7

Reactant 4

HCID 6344DichloromethaneHCID 11430Potassium CarbonateHCID 867294684-((4-Fluorophenyl)amino)-7-methoxyquinazolin-6-olHCID 867294832-(3-chloropropyl)hexahydropyrano[3,4-c]pyrrol-4(2H)-one

Product 1

HCID 867295252-(3-((4-((4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)propyl)hexahydropyrano[3,4-c]pyrrol-4(2H)-oneYield 37.3%

Reagents, catalysts & solvents 2

HCID 67553Tetrabutylammonium IodideCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
90 °C

Procedure

To a solution of 2-(3-chloropropyl)hexahydropyrano[3,4-c]pyrrol-4(2H)-one (0.25 g) in DMF (8 mL) was added K2CO3 (3.0 eq), 4-((4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (0.38 g) and tetrabutylammonium iodide (0.1 eq). The reaction mixture was heated to 90° C. and stirred for 10 h. To the mixture was added CH2Cl2 (100 mL). The mixture was washed with water and brine. The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) CH2Cl2/CH3OH) to give the product (0.20 g, 32.50%), HPLC: 97.35%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 467.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 2.06-2.12 (m, 4H), 2.35 (d, J=2.92 Hz, 1H), 2.51-2.58 (m, 3H), 2.76-2.79 (m, 2H), 2.97-3.02 (m, 1H), 3.49-3.50 (m, 1H), 3.52 (s, 1H), 4.00 (s, 3H), 4.18 (d, J=1.80 Hz, 1H), 4.21-4.24 (m, 1H), 4.35-4.40 (m, 1H), 7.13 (t, J=8.80 Hz, 1H), 7.24 (d, J=9.48 Hz, 1H), 7.41 (s, 1H), 7.68 (m, 2H), 7.95-7.98 (m, 1H), 8.28 (s, 1H), 8.63 (s, 1H) ppm.

Workup

  1. washThe mixture was washed with water and brine
  2. dry with materialThe organic layer was dried over anhydrous Na2SO4
  3. filtrationfiltered
  4. concentrationThe filtrate was concentrated in vacuo
  5. customthe residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) CH2Cl2/CH3OH)

Sources & evidence

ORD record
ord-a51454ae5fc041f08858fe9fdfee4f30
Source dataset
uspto-grants-2015_11
Patent number
US09181277B2

Reaction notes

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