Compounds 5-7 Were Synthesized As Shown in Scheme 1

Compounds 5-7 were synthesized as shown in scheme 1.

Scheme 1

n-BuLi (2.5 M, 15.8 mL, 39.7 mmol) was added drop wise to a cold solution (-78 °C) of 2-(4-chlorophenyl)thiophene (9.0 g, 33 mmol) in dry THF (100 mL). Reaction temperature was increased to –50 °C and added a solution of bis(pinacolato)diboron (10.0 g, 39.7 mmol) in THF (20 mL) to the above solution and stirred at room temperature for 16 h. Reaction mixture was extracted with ethyl acetate (300 mL), washed with water followed by brine solution, dried over anhydrous Na2SO4 and concentrated to give 2-[5-(4-chlorophenyl)thiophen-2-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as dark brown semi solid. 1H NMR (400 MHz, CD3COCD3): δ 7.7 (d, J=8.4Hz, 2H), 7.50 (d, J=4.4Hz, 2H), 7.4 (d, J=8.8Hz, 2H), 1.23 (s, 12H). A freshly prepared aqueous 2M sodium carbonate (40 mL) was degassed by bubbling argon for 30 min and added a solution of 2-(5-(4-chlorophenyl)thiophenyl-2-yl)-4,4,5,5-tetramethyl-1-3-2-dioxaborolone (2 g, 6.25 mmol) in toluene (60 mL) followed by 2,4-dichloro-quinazoline (1.5 g, 7.5 mmol) and the degassing was continued for additional 10 min. To the above mixture added Pd(PPh3)4 (0.352 g 3mol%) and heated to 90 °C for about 2 h. The reaction mixture was cooled and separated the organic layer and aqueous layer was washed twice with ethyl acetate (2 x 80 mL). The combined organic layer was washed with saturated brine, dried over anhydrous Na2SO4 and concentrated. The crude compound was recrystallized from hexane-diethyl ether-chloroform (5:5:2) to get brown colored solid. MS: M-1 357. 1H NMR (400 MHz, CDCl3): δ 8.53 (d, J=8.4Hz, 1H), 8.02 (d, J=8.4Hz, 1H), 7.97 (d, J=6.4Hz, 1H), 7.92 (d, J=4.0 Hz, 2H) 7.65 (d, J=4.2Hz, 2H), 7.42 (d, J=4.2Hz, 2H), 7.42-7.45(m, 1H).

A solution of 2-chloro-4-[5-(4-chloro-phenyl)-thiophen-2-yl]-quinazoline (100 mol%), corresponding amine (200 mol%) and triethylamine (200 mol%) in DMSO was stirred in a sealed tube for 16 h at 100 °C (or 10-15 min at 160 °C in microwave). Solvent was removed under vacuum and extracted with ethyl acetate and washed with water, brine and dried over anhydrous Na2SO4. The organic layer was concentrated and the crude compound was chromatographed on silica gel eluting with stepwise gradient of cyclohexane / ethyl acetate to afford pure corresponding compounds.

Compound 5: MS: M+1 477. 1H NMR (400 MHz, CDCl3): δ 8.3 (br d, 1 H), 8.0 (br d, 1 H), 7.80-7.65 (m, 4H), 7.54 (d, J=8 Hz, 2H), 7.45 (br d, 1H), 7.24 (m, 2H), 4.38 (br m, 1 H), 1.83 (d, J=10.8 Hz, 2H), 1.45-1.00 (m, 14H).

Compound 6: MS: M+1 429. 1H NMR (400 MHz, CDCl3): δ 8.72 (s, 1H), 8.52 (d, J=4Hz, 1H), 8.28 (d, J=8Hz, 1H), 7.79-7.72 (m, 2H), 7.7-7.67 (m, 2H), 7.76 (d, J=4Hz, 2H), 7.63-7.38 (m, 3H), 7.29 (d, J=6.8Hz, 1H), (5.66-5.56 (s, br 1H), 4.82 (d, J=6Hz, 2H).