[Synthesis]
Synthesis of (E)-2-methoxy-N-(3-(4-((3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)amino)quinazolin-6-yl)allyl)-N-(3-(4-((3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)amino)quinazolin-6-yl)quinazolin-6-yl)allyl)amide from 6-iodo-N-(3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)amino)quinazolin-6-yl)allyl)acetamide as raw material (CAS:537705-07-0) The general procedure for acetamide is as follows:
1. 2-Methyl-2-butene (0.59 mL, 5.60 mmol, 2.8 eq.) was added dropwise to a BH3?THF complex (1.0 M solution, 3.0 mL, 3.0 mmol, 1.5 eq.) cooled to 0-5°C over a period of 1 hour under nitrogen protection. The reaction mixture was stirred at this temperature for 30 min.
2. 2-Methoxy-propionamide acetate (255 mg, 2 mmol, 1.0 eq.) dissolved in dry THF (1 mL) was added to the reaction mixture over 15 minutes. The ice bath was removed and the reaction mixture was slowly warmed to room temperature over 20 min followed by heating at 35°C for 1 hr.
3. K2CO3 (0.55 g, 4 mmol, 2.0 eq.) was dissolved in degassed H2O (1.2 mL) and added dropwise to the reaction mixture over 30 min. Gas release was observed during dropwise addition.
4. 6-Iodo-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazoline (1.41 g, 3 mmol, 1.5 eq.) was added to the yellow suspension in three batches. PPh3 (21 mg, 0.08 mmol, 4 mol%) and Pd(OAc)2 (4.5 mg, 0.02 mmol, 1 mol%) were then added separately and the reaction mixture was heated to reflux (65-68°C).
5. After about 30 min, the reaction mixture changed to a yellow solution and the reaction progress was monitored by HPLC. after 18 h, the reaction mixture was cooled to room temperature.
6. Half-saturated NaCl solution (10 mL) and EtOAc (10 mL) were added, the organic phase was separated, washed with H2O (5 mL), and concentrated at 50°C and a pressure below 200 mbar.
7. Purification by silica gel column chromatography (EtOAc/MeOH = 9/1) afforded (E)-2-methoxy-N-(3-(4-(4-((3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)amino)quinazolin-6-yl)allyl)acetamide as light yellow crystals (0.55 g, 59%). rf = 0.16 (EtOAc/ MeOH = 9/1).
NMR data:
1H-NMR (CDCl3, 250 MHz): δ = 8.71 (s, 1H, H-2), 8.25 (d, J = 1.7 Hz, 1H, H-8), 7.90 (s, 1H, H-7), 7.82 (s, 1H, NH), 7.79 (s, 1H, H-5), 7.66 (d, J = 2.5 Hz, 1H, H-4'). 7.54 (dd, J1 = 8.7 Hz, J2 = 2.6 Hz, 1H, H-5'), 7.15-7.07 (m, 2H, H-5', H-6'), 6.91 (dt, J = 8.7 Hz, 1H, H-2'), 6.83 (bt, 1H, NH), 6.65 (dt, J = 15.9 Hz, 1H, H-9), 6.34 and 6.29 (dt, J1 = 15.9 Hz, J2 = 6.1 Hz, 1H, H-10), 4.14 (dt, J = 6.1 Hz, 2H, CH2OMe), 3.97 (s, 2H, CH2NH), 3.45 (s, 3H, OCH3), 2.53 (s, 3H, CH3), 2.29 (s, 3H, CH3).
13C-NMR (CDCl3, 75 MHz): δ = 169.76 (C=O), 157.90, 154.93, 152.367, 152.23, 150.90, 149.74, 139.34, 134.73, 134.63, 131.16, 130.77, 130.36, 128.85, 129.98, 125.47, 124.66, 123.65, 121.32, 119.51, 119.13, 115.39, 71.96, 59.26, 40.84, 23.57, 16.41.
The analytes were analyzed by reversed-phase high performance liquid chromatography (HPLC) using a Symmetry Shield RP18 column, 75 x 4.6 mm, flow rate of 1.0 mL/min, detection wavelengths of 205/210/220/245 nm, temperature 25°C, injection volume of 10 μL, about 0.5% ACN/H2O solution, eluent B was ACN, eluent C was 0.01 mmol NH4OAc in H2O, pH = 6.0), gradient elution conditions: 0 min B = 30%, C = 70%; 20 min B = 85%, C = 15%. Under these conditions, the retention time (tR) of (E)-2-methoxy-N-(3-(4-((3-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)amino)quinazolin-6-yl)allyl)acetamide was 6.02 min. |