4-(4-bromo-2-fluorophenylamino)-6-methoxyquinazolin-7-ol

4-(4-Bromo-2-fluorophenylamino)-6-methoxyquinazolin-7-ol Intermediate 2-3 (1.30 g, 2.86 mmol) was dissolved in trifluoroacetic acid (15 mL) and the solution was heated to reflux for 1.5 hours. The solution was cooled to room temperature and concentrated under reduced pressure. Methanol (20 mL) was added to the remaining brown solid and the pH was adjusted to 11 with concentrated ammonium hydroxide. The mixture was concentrated under reduced pressure and dried under high vacuum before purification by flash column chromatography on silica gel (20 g), eluting with 5-20percent methanol in dichloromethane. The experiment generated 2-4 (1.03 g, 99percent yield) as a light yellow solid. (at)H NMR (300 MHz, DMSO-d6): No. 10.5 (br s, 1 H), 9.53 (br s, 1 H), 8.34 (s, 1 H), 7.81 (s, 1 H), 7.63 (d, 1 H, J = 9.6 Hz), 7.54 (dd, 1 H, J = 8.4, 7.8 Hz), 7.44 (d, 1 H, J = 8.4 Hz), 7.12 (s, 1 H), 3.95 (s, 3H). After the reaction mixture was evaporated, the mixture was added cold aqueous NaHCO3 and concentrated NH3.H2O, and pH of solution was then adjusted to 10. The resulted precipitate was filtered, washed with water and Et2O, and dried under vacuum to give 3a (2.91 g, 91percent) as a white solid.A solution of 7-(Benzyloxy)-N-(4-bromo-2-fluorophenyl)-6-methoxyquinazolin-4-amine (3.5 g, 6.16 mmol, 1.00 equiv) and trifluoroacetic acid (30 mL) was heated at reflux for about 1 hour and then cooled to about 0° C. A solution of 7-BENZYLOXY-4- (4-BROMO-2-FLUOROANILINO)-6-METHOXYQUINAZOLINE hydrochloride (9.4g, 19. 1MMOL) in TFA (90MOL) was heated at reflux for 50 minutes. The mixture was allowed to cool and was poured on to ice. The resulting precipitate was collected by filtration and dissolved in methanol (70ML). The solution was adjusted to pH9-10 with concentrated aqueous ammonia solution. The mixture was concentrated to half initial volume by evaporation. The resulting precipitate was collected by filtration, washed with water and then ether, and dried under vacuum to give 4- (4-BROMO-2-FLUOROANILINO)-7-HYDROXY-6- methoxyquinazoline (5.66g, 82percent). H NMR Spectrum: (DMSOd6; CD3COOD) 3.95 (s, 3H); 7.09 (s, 1H); 7.48 (s, 1H); 7.54 (t, 1H); 7.64 (d, 1H); 7.79 (s, 1H); 8.31 (s, 1H) MS-ESI: 366 [MH] + Elemental analysis: Found C 49.5 H 3.1 N 11.3 CISHNN302BRF Requires C 49.5 H 3.0 N 11.5percentThe compound (2.3g, 5.06 mmol) obtained in Potassium carbonate (414mg, 3mmol) was added to a suspension of 7-hydroxy-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline (9.7 g), sodium hydroxide (47% w/w, 5.0ml) and Adogen 464 (1.5 g) were added to water (50 ml) with stirring. l-(tert-butoxycarbonyl)-4-(4-methylphenylsulfonyloxymethyl)piperidine (10.0 g) as a solution in toluene (35 ml) was then added to the reaction mixture and heated to 700C for 18 hours. The reaction mixture was then cooled to 2O0C and the product was isolated by filtration. The product was then washed with toluene (20 ml) and dried at 500C. Yield: 8.72 g, 77%; NMR Spectrum (DMSOd6) 1.15-1.3 (m, 2H), 1.46 (s, 9H), 1.8 (d, 2H), 2.0- 2.1 (m, IH), 2.65-2.9 (m, 2H) 3.95 (s, 3H), 4.02 (br s, 2H), 4.05 (d, 2H), 7.2 (s, IH), 7.48 (d, IH), 7.55 (t, IH), 7.65 (d, IH), 7.8 (d, IH), 8.35 (s, IH), 9.55 (br s, IH); Mass Spectrum [ESI] (M+H)+ - 561-563Potassium carbonate (1.5 g, 10.8 mmol, 2.00 equiv) was added to a solution of 4-(4-bromo-2-fluorophenylamino)-6-methoxyquinazolin-7-ol (2.0 g, 5.22 mmol, 1.00 equiv) and N, N-dimethylformamide (20 mL). After stirring at ambient temperature for about 10 minutes, tert-butyl 4-((tosyloxy)methyl)piperidine-1-carboxylate (2.3 g, 5.91 mmol, 1.15 equiv) was then added. The resulting solution was stirred at about 95 C. for about 2 hours, and then diluted with ice-cold water (40 mL). The resulting solids were collected by filtration, and purified by silica gel column chromotagraphy (ethyl acetate/petroleum ether 1:5) to give the title product as a white solid (1.3 g, yield 40%). LC-MS: m/z=561/563 (MH)+.Add 7.3 (20 mmol) of 4-((4-bromo-2-fluorophenyl)amino)-6-methoxy-7-ol (Compound 6) to 200 mL of DMF and heat to 75 C, add 8.9 dropwise g (24 mmol) 4-((toluenesulfonyloxy)methyl)piperidine-1-carboxylic acid tert-butyl ester (Compound 7), The dropping time is about 1 h; during the dropping process, Add 1.4g (10mmol) potassium carbonate in batches (in 6 batches, Added within 1h), The reaction was continued for 6 h after the addition was completed.After the reaction is over, Filter, filter cake with a little DMF rinse, The filtrate was concentrated under reduced pressure.The concentrate is added to 100g of ice water and stirred.Filtration gave the target product.4-(4-Bromo-2-fluorophenylamino)-6-methoxyquinazolin-7-ol Intermediate 2-3 (1.30 g, 2.86 mmol) was dissolved in trifluoroacetic acid (15 mL) and the solution was heated to reflux for 1.5 hours. The solution was cooled to room temperature and concentrated under reduced pressure. Methanol (20 mL) was added to the remaining brown solid and the pH was adjusted to 11 with concentrated ammonium hydroxide. The mixture was concentrated under reduced pressure and dried under high vacuum before purification by flash column chromatography on silica gel (20 g), eluting with 5-20% methanol in dichloromethane. The experiment generated 2-4 (1.03 g, 99% yield) as a light yellow solid. (at)H NMR (300 MHz, DMSO-d6): No. 10.5 (br s, 1 H), 9.53 (br s, 1 H), 8.34 (s, 1 H), 7.81 (s, 1 H), 7.63 (d, 1 H, J = 9.6 Hz), 7.54 (dd, 1 H, J = 8.4, 7.8 Hz), 7.44 (d, 1 H, J = 8.4 Hz), 7.12 (s, 1 H), 3.95 (s, 3H). ¹3C NMR (75 MHz, DMSO-d6): No. 156.77, 156.49, 152.92, 152.62, 148.62, 146.74, 129.40, 127.39, 126.46 (d, J = 12 Hz), 119.23 (d, J = 23.2 Hz), 117.4 (d, J = 8.3 Hz), 109.96, 108.08, 102.23, 56.09.After the reaction mixture was evaporated, the mixture was added cold aqueous NaHCO3 and concentrated NH3.H2O, and pH of solution was then adjusted to 10. The resulted precipitate was filtered, washed with water and Et2O, and dried under vacuum to give 3a (2.91 g, 91%) as a white solid.A solution of 7-(Benzyloxy)-N-(4-bromo-2-fluorophenyl)-6-methoxyquinazolin-4-amine (3.5 g, 6.16 mmol, 1.00 equiv) and trifluoroacetic acid (30 mL) was heated at reflux for about 1 hour and then cooled to about 0 C. The resulting solids were collected by filtration, and then dissolved in methanol (50 mL). The pH value of the resulting solution was then adjusted to 9-10 with ammonium hydroxide (25%). The resulting mixture was concentrated in vacuo and washed water and ether to give the title product as a gray solid (2.0 g, yield 85%). 1H NMR (300 MHz, DMSO) delta: 10.35 (s, 1H), 9.46 (s, 1H), 9.30 (s, 1H), 7.79 (s, 1H), 7.66 (dd, J=9.9, 1.8Hz, 1H), 7.45-7.57 (m, 2H), 7.07 (s, 1H), 3.96 (s, 3H); LC-MS: m/z=364/366 (MH)+.A solution of 7-BENZYLOXY-4- (4-BROMO-2-FLUOROANILINO)-6-METHOXYQUINAZOLINE hydrochloride (9.4g, 19. 1MMOL) in TFA (90MOL) was heated at reflux for 50 minutes. The mixture was allowed to cool and was poured on to ice. The resulting precipitate was collected by filtration and dissolved in methanol (70ML). The solution was adjusted to pH9-10 with concentrated aqueous ammonia solution. The mixture was concentrated to half initial volume by evaporation. The resulting precipitate was collected by filtration, washed with water and then ether, and dried under vacuum to give 4- (4-BROMO-2-FLUOROANILINO)-7-HYDROXY-6- methoxyquinazoline (5.66g, 82%). H NMR Spectrum: (DMSOd6; CD3COOD) 3.95 (s, 3H); 7.09 (s, 1H); 7.48 (s, 1H); 7.54 (t, 1H); 7.64 (d, 1H); 7.79 (s, 1H); 8.31 (s, 1H) MS-ESI: 366 [MH] + Elemental analysis: Found C 49.5 H 3.1 N 11.3 CISHNN302BRF Requires C 49.5 H 3.0 N 11.5%The compound (2.3g, 5.06 mmol) obtained in Step 2: General procedure: The quinazolinamines 4a-4g (1 eq) was dissolved in 10 mL DMF, potassium carbonate (2 eq) was added and stirred at 50 C for 0.5 h.Intermediate 8a-8c (1 eq) was dissolved in DMF and then addeddropwise to reaction mixture. The reaction was monitored by TLC.The mixture was cooled to room temperature after reactantconsumed completely and then poured into water with stirring for0.5 h. Filtrated and dissolved the precipitate with methanol, evaporatedsolvent under reduced pressure after dryness with anhydrousNa2SO4. The residue was recrystallized in methanol to obtaintarget compounds.

4-[(4-Bromo-2-fluorophenyl)amino]-6-methoxy-7-Quinazolinol is used in the synthesis of [18F]-(R)-FEPAQ, a potential PET imaging agent for VEGFR2. This would be helpful in the imaging of VEGFR in cancer patients.

Molecular Weight:364.17
XLogP3:3.8
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:6
Rotatable Bond Count:3
Exact Mass:363.00187
Monoisotopic Mass:363.00187
Topological Polar Surface Area:67.3
Heavy Atom Count:22
Complexity:379
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes