Dichloromethane → N-(3-chloro-4-fluorophenyl)-6-(3-(hexahydrocyclopenta[c]pyrrol-2(1H)-yl)propoxy)-7-methoxyquinazolin-4-amine

HRID 712435Notes

Reaction equation

HRID 712435 reaction equation
Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH:8]2[CH2:10][CH2:11][CH2:12][CH:7]2[CH2:6]1.C([O-])([O-])=O.[K+].[K+].[Cl:19][C:20]1[CH:21]=[C:22]([NH:27][C:28]2[C:37]3[C:32](=[CH:33][C:34]([O:39][CH3:40])=[C:35]([OH:38])[CH:36]=3)[N:31]=[CH:30][N:29]=2)[CH:23]=[CH:24][C:25]=1[F:26].C(Cl)Cl>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:19][C:20]1[CH:21]=[C:22]([NH:27][C:28]2[C:37]3[C:32](=[CH:33][C:34]([O:39][CH3:40])=[C:35]([O:38][CH2:2][CH2:3][CH2:4][N:5]4[CH2:9][CH:8]5[CH2:10][CH2:11][CH2:12][CH:7]5[CH2:6]4)[CH:36]=3)[N:31]=[CH:30][N:29]=2)[CH:23]=[CH:24][C:25]=1[F:26]

Participants

7

Reactant 4

HCID 6344DichloromethaneHCID 11430Potassium CarbonateHCID 104712174-[(3-Chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-olHCID 867294842-(3-Chloropropyl)octahydrocyclopenta[c]pyrrole

Product 1

HCID 71571781N-(3-chloro-4-fluorophenyl)-6-(3-(hexahydrocyclopenta[c]pyrrol-2(1H)-yl)propoxy)-7-methoxyquinazolin-4-amineYield 75.59%

Reagents, catalysts & solvents 2

HCID 67553Tetrabutylammonium IodideCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
90 °C

Procedure

To a solution of 2-(3-chloropropyl)octahydrocyclopenta[c]pyrrole (2.00 g, 1.2 eq) in DMF (15 mL) was added K2CO3 (2.46 g, 2.0 eq), 4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (2.84 g, 1.0 eq) and tetrabutylammonium iodide (0.1 eq). The reaction mixture was stirred at 90° C. for 12 h under N2, and 100 mL of CH2Cl2 was added. The mixture was washed with water followed by brine. The mixture was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) CH2Cl2/CH3OH) to afford the title compound (2.23 g, 75.59%), HPLC: 94.23%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 472.0 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.40-1.43 (m, 2H), 1.58-1.65 (m, 4H), 2.01 (t, J=8.92 Hz, 2H), 2.10 (t, J=13.48 Hz, 2H), 2.57-2.60 (m, 4H), 2.90 (t, J=16.32 Hz, 2H), 3.49 (s, 2H), 4.00 (s, 3H), 4.21 (t, J=12.00 Hz, 2H), 7.13-7.20 (m, 2H), 7.57 (d, J=1.28 Hz, 2H), 7.59-7.60 (m, 1H), 7.91 (m, 1H), 7.93 (m, 1H), 8.65 (s, 1H) ppm.

Workup

  1. washThe mixture was washed with water
  2. dry with materialThe mixture was dried over anhydrous Na2SO4
  3. concentrationconcentrated in vacuo
  4. customThe residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) CH2Cl2/CH3OH)

Sources & evidence

ORD record
ord-93ff69be93514aeba1f3051fc8cc9e8e
Source dataset
uspto-grants-2015_11
Patent number
US09181277B2

Reaction notes

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