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

HRID 712433Notes

Reaction equation

HRID 712433 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+].[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][C:30]2[C:39]3[C:34](=[CH:35][C:36]([O:41][CH3:42])=[C:37]([OH:40])[CH:38]=3)[N:33]=[CH:32][N:31]=2)[CH:25]=[CH:26][C:27]=1[F:28].C(Cl)Cl>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][C:30]2[C:39]3[C:34](=[CH:35][C:36]([O:41][CH3:42])=[C:37]([O:40][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:38]=3)[N:33]=[CH:32][N:31]=2)[CH:25]=[CH:26][C:27]=1[F:28]

Participants

7

Reactant 4

HCID 6344DichloromethaneHCID 11430Potassium CarbonateHCID 104712174-[(3-Chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-olHCID 867294832-(3-chloropropyl)hexahydropyrano[3,4-c]pyrrol-4(2H)-one

Product 1

HCID 867294822-(3-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)propyl) hexahydropyrano[3,4-c]pyrrol-4(2H)-oneYield 28.8%

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 (0.19 g) in DMF (8 mL) was added K2CO3 (3.0 eq), 4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (0.25 g) and tetrabutylammonium iodide (0.1 eq). The reaction mixture was heated at 90° C. for 20 h, and then treated with CH2Cl2 (100 mL). The mixture was washed with water (100 mL×3) and brine (100 mL), and dried over anhydrous Na2SO4. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) CH2Cl2/CH3OH) to give the title compound (113 mg, 19.62%), HPLC: 95.64%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 502.0 (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, 1H), 7.95-7.98 (m, 1H), 8.28 (s, 1H), 8.63 (s, 1H) ppm.

Workup

  1. washThe mixture was washed with water (100 mL×3) and brine (100 mL)
  2. dry with materialdried over anhydrous Na2SO4
  3. filtrationThe mixture was filtered
  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-64d1c6e0044142c09b1d6cbdc181bab1
Source dataset
uspto-grants-2015_11
Patent number
US09181277B2

Reaction notes

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