(4aR,7aR)-3,4a,5,6,7,7a-hexahydro-2H-[1,4]dioxino[2,3-c]pyrrole

反应条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of (4aR,7aR)-hexahydro-2H-[1,4]dioxino[2,3-c]pyrrole (129.0 mg, 1.0 mmol), K2CO3 (217.0 mg, 1.56 mmol), tetrabutylammoniumiodide (44.0 mg, 0.12 mmol) and N-(3-chloro-4-fluorophenyl)-6-(3-chloropropoxy)-7-methoxyquinazolin-4-amine (475.0 mg, 1.20 mmol) in 15 mL of DMF was stirred for 9 h at 60° C., then poured into 10 mL of ice-water and extracted with CH2Cl2. The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was chromatographed with a silica gel column (eluting agent: 30:1 (v/v) DCM/MeOH) to give the title compound as a pale yellow solid (120 mg, 24.50%), HPLC: 94.43%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 489.9 (M+1); 1H NMR (400 MHz, CDCl3) δ: 2.04 (m, 2H), 2.6 (br, 1H), 2.72 (m, 2H), 2.82 (m, 2H), 3.04 (m, 2H), 3.64 (t, J=6.08 Hz, 2H), 3.80 (m, 4H), 3.98 (s, 3H), 4.16 (t, J=6.48 Hz, 2H), 7.14 (t, J=8.76 Hz, 1H), 7.23 (d, J=7.8 Hz, 1H), 7.58 (m, 2H), 7.90 (dd, J1=6.48 Hz, J2=2.56 Hz, 1H), 8.65 (s, 1H). extracted with CH2Cl2 The organic phase was dried over anhydrous Na2SO4 concentrated in vacuo The residue was chromatographed with a silica gel column (eluting agent: 30:1 (v/v) DCM/MeOH)

反应条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of (4aR,7aR)-hexahydro-2H-[1,4]dioxino[2,3-c]pyrrole (129.0 mg, 1.0 mmol), K2CO3 (217.0 mg, 1.56 mmol), tetrabutylammoniumiodide (44.0 mg, 0.12 mmol) and N-(3-chloro-4-fluorophenyl)-6-(3-chloropropoxy)-7-methoxyquinazolin-4-amine (475.0 mg, 1.20 mmol) in 15 mL of DMF was stirred for 9 h at 60° C., then poured into 10 mL of ice-water and extracted with CH2Cl2. The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was chromatographed with a silica gel column (eluting agent: 30:1 (v/v) DCM/MeOH) to give the title compound as a pale yellow solid (120 mg, 24.50%), HPLC: 94.43%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 489.9 (M+1); 1H NMR (400 MHz, CDCl3) δ: 2.04 (m, 2H), 2.6 (br, 1H), 2.72 (m, 2H), 2.82 (m, 2H), 3.04 (m, 2H), 3.64 (t, J=6.08 Hz, 2H), 3.80 (m, 4H), 3.98 (s, 3H), 4.16 (t, J=6.48 Hz, 2H), 7.14 (t, J=8.76 Hz, 1H), 7.23 (d, J=7.8 Hz, 1H), 7.58 (m, 2H), 7.90 (dd, J1=6.48 Hz, J2=2.56 Hz, 1H), 8.65 (s, 1H). extracted with CH2Cl2 The organic phase was dried over anhydrous Na2SO4 concentrated in vacuo The residue was chromatographed with a silica gel column (eluting agent: 30:1 (v/v) DCM/MeOH)

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of (4aR,7aR)-benzyl tetrahydro-2H-[1,4]dioxino[2,3-c]pyrrole-6(3H)-carboxylate (140.0 mg, 0.53 mmol) and 10% Pd/C (0.56 mg, 0.053 mmol) in THF (6 mL) was stirred for 5.0 h at 50° C. The resulted mixture was filtered. The filtrate was concentrated in vacuo and the residue was used for the next step without further purification. The resulted mixture was filtered The filtrate was concentrated in vacuo the residue was used for the next step without further purification

反应条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of (4aR,7aR)-hexahydro-2H-[1,4]dioxino[2,3-c]pyrrole (129.0 mg, 1.0 mmol), K2CO3 (217.0 mg, 1.56 mmol), tetrabutylammoniumiodide (44.0 mg, 0.12 mmol) and N-(3-chloro-4-fluorophenyl)-6-(3-chloropropoxy)-7-methoxyquinazolin-4-amine (475.0 mg, 1.20 mmol) in 15 mL of DMF was stirred for 9 h at 60° C., then poured into 10 mL of ice-water and extracted with CH2Cl2. The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was chromatographed with a silica gel column (eluting agent: 30:1 (v/v) DCM/MeOH) to give the title compound as a pale yellow solid (120 mg, 24.50%), HPLC: 94.43%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 489.9 (M+1); 1H NMR (400 MHz, CDCl3) δ: 2.04 (m, 2H), 2.6 (br, 1H), 2.72 (m, 2H), 2.82 (m, 2H), 3.04 (m, 2H), 3.64 (t, J=6.08 Hz, 2H), 3.80 (m, 4H), 3.98 (s, 3H), 4.16 (t, J=6.48 Hz, 2H), 7.14 (t, J=8.76 Hz, 1H), 7.23 (d, J=7.8 Hz, 1H), 7.58 (m, 2H), 7.90 (dd, J1=6.48 Hz, J2=2.56 Hz, 1H), 8.65 (s, 1H). extracted with CH2Cl2 The organic phase was dried over anhydrous Na2SO4 concentrated in vacuo The residue was chromatographed with a silica gel column (eluting agent: 30:1 (v/v) DCM/MeOH)

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of (4aR,7aR)-benzyl tetrahydro-2H-[1,4]dioxino[2,3-c]pyrrole-6(3H)-carboxylate (140.0 mg, 0.53 mmol) and 10% Pd/C (0.56 mg, 0.053 mmol) in THF (6 mL) was stirred for 5.0 h at 50° C. The resulted mixture was filtered. The filtrate was concentrated in vacuo and the residue was used for the next step without further purification. The resulted mixture was filtered The filtrate was concentrated in vacuo the residue was used for the next step without further purification