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

Temperature

90 °C

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.

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)

ORD record

ord-93ff69be93514aeba1f3051fc8cc9e8e

Source dataset

uspto-grants-2015_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09181277B2