tert-butyl N-(3-bromo-2-fluorophenyl)carbamate

Conditions: temp:106.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of tert-butyl 3-bromo-2-fluorophenylcarbamate (6.0 g, 20.7 mmol) in 4N HCl (30 mL) in dioxane was stirred at ambient temperature for 2 hours. The solvent was removed under reduced pressure. The residue was dissolved in 6 N HCl (100 mL) and (E)-but-2-enal (2.96 ml, 36.2 mmol) was added dropwise at 106° C. The reaction was stirred at 106° C. for 2 hours. After cooling to ambient temperature, the reaction mixture was basified with ammonium hydroxide to about pH 12, extracted with DCM (2×100 mL), dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (5:1 hexane/ethyl acetate) to give 7-bromo-8-fluoro-2-methylquinoline (2.99 g, 60.2%) as a solid. The solvent was removed under reduced pressure The residue was dissolved in 6 N HCl (100 mL) After cooling to ambient temperature extracted with DCM (2×100 mL) dried (sodium sulfate) filtered concentrated under reduced pressure The residue was purified by flash chromatography on silica gel (5:1 hexane/ethyl acetate)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 3-bromo-2-fluorobenzoic acid (6.86 g, 31.32 mm 1), triethylamine (5.24 mL, 37.59 mmol) and DPPA (7.45 mL, 34.46 mmol) in t-BuOH (30 mL) was stirred at reflux for 20 hours. After cooling to ambient temperature, the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (4:1 hexane/ethyl acetate) to give tert-butyl 3-bromo-2-fluorophenylcarbamate (6.0 g, 66.0%) as an oil. at reflux for 20 hours the solvent was removed under reduced pressure The residue was dissolved in ethyl acetate (100 mL) washed with brine dried (sodium sulfate) filtered concentrated under reduced pressure The residue was purified by flash chromatography on silica gel (4:1 hexane/ethyl acetate)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a microwave tube N-Boc-3-bromo-2-fluoro-aniline (300 mg, 1.034 mmol) was dissolved in a 9:1 DME/H2O mixture (12 mL) and argon was bubbled through the solution for 10 minutes. 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (prepared as described in WO2010/010154) (576 mg, 2.071 mmol, 2 eq) was then added, followed by cesium carbonate (1.0 g, 3 eq) and Pd(dppf)Cl2.CH2Cl2 (84 mg, 14.6 mmol, 0.1 eq) and the reaction mixture was irradiated at 100° C. for 30 minutes. A further addition of 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1 eq) was made and a second microwave cycle was performed at 100° C. for 30 min. The mixture was then filtered over a Celite pad, which was washed with AcOEt. The filtrate was washed with water and brine, dried over Na2SO4 and evaporated to dryness. The crude was purified by chromatography on silica gel (Hex/AcOEt 8:2) to give 570 mg of {2-Fluoro-3-[2-(tetrahydro-pyran-2-yl)-2H-pyrazol-3-yl]-phenyl}-carbamic acid tert-butyl ester contaminated by N-tetrahydropyranyl-pyrazole (NMR title about 57%). HPLC (254 nm): Rt: 6.82 min; 1H NMR (DMSO-d6) Shift: 9.09 (s, 1H), 7.72 (t, J=7.6 Hz, 1H), 7.62 (d, J=1.8 Hz, 1H), 7.22-7.29 (m, 1H), 7.16-7.22 (m, 1H), 6.42-6.45 (m, 1H), 5.09-5.15 (m, 1H), 3.86-3.95 (m, 1H), 3.35-3.46 (m, 1H), 1.51-1.73 (many m, 6H), 1.48 (s, 9H); HRMS (ESI) calcd for C19H25FN3O3 [M+H]+ 362.1875. found 362.1874. was bubbled through the solution for 10 minutes The mixture was then filtered over a Celite pad, which was washed with AcOEt The filtrate was washed with water and brine dried over Na2SO4 evaporated to dryness The crude was purified by chromatography on silica gel (Hex/AcOEt 8:2)

Conditions: temp:106.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of tert-butyl 3-bromo-2-fluorophenylcarbamate (6.0 g, 20.7 mmol) in 4N HCl (30 mL) in dioxane was stirred at ambient temperature for 2 hours. The solvent was removed under reduced pressure. The residue was dissolved in 6 N HCl (100 mL) and (E)-but-2-enal (2.96 ml, 36.2 mmol) was added dropwise at 106° C. The reaction was stirred at 106° C. for 2 hours. After cooling to ambient temperature, the reaction mixture was basified with ammonium hydroxide to about pH 12, extracted with DCM (2×100 mL), dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (5:1 hexane/ethyl acetate) to give 7-bromo-8-fluoro-2-methylquinoline (2.99 g, 60.2%) as a solid. The solvent was removed under reduced pressure The residue was dissolved in 6 N HCl (100 mL) After cooling to ambient temperature extracted with DCM (2×100 mL) dried (sodium sulfate) filtered concentrated under reduced pressure The residue was purified by flash chromatography on silica gel (5:1 hexane/ethyl acetate)

Conditions: temp:106.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of tert-butyl 3-bromo-2-fluorophenylcarbamate (6.0 g, 20.7 mmol) in 4N HCl (30 mL) in dioxane was stirred at ambient temperature for 2 hours. The solvent was removed under reduced pressure. The residue was dissolved in 6 N HCl (100 mL) and (E)-but-2-enal (2.96 ml, 36.2 mmol) was added dropwise at 106° C. The reaction was stirred at 106° C. for 2 hours. After cooling to ambient temperature, the reaction mixture was basified with ammonium hydroxide to about pH 12, extracted with DCM (2×100 mL), dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (5:1 hexane/ethyl acetate) to give 7-bromo-8-fluoro-2-methylquinoline (2.99 g, 60.2%) as a solid. The solvent was removed under reduced pressure The residue was dissolved in 6 N HCl (100 mL) After cooling to ambient temperature extracted with DCM (2×100 mL) dried (sodium sulfate) filtered concentrated under reduced pressure The residue was purified by flash chromatography on silica gel (5:1 hexane/ethyl acetate)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 3-bromo-2-fluorobenzoic acid (6.86 g, 31.32 mm 1), triethylamine (5.24 mL, 37.59 mmol) and DPPA (7.45 mL, 34.46 mmol) in t-BuOH (30 mL) was stirred at reflux for 20 hours. After cooling to ambient temperature, the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (4:1 hexane/ethyl acetate) to give tert-butyl 3-bromo-2-fluorophenylcarbamate (6.0 g, 66.0%) as an oil. at reflux for 20 hours the solvent was removed under reduced pressure The residue was dissolved in ethyl acetate (100 mL) washed with brine dried (sodium sulfate) filtered concentrated under reduced pressure The residue was purified by flash chromatography on silica gel (4:1 hexane/ethyl acetate)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 3-bromo-2-fluorobenzoic acid (6.86 g, 31.32 mm 1), triethylamine (5.24 mL, 37.59 mmol) and DPPA (7.45 mL, 34.46 mmol) in t-BuOH (30 mL) was stirred at reflux for 20 hours. After cooling to ambient temperature, the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (4:1 hexane/ethyl acetate) to give tert-butyl 3-bromo-2-fluorophenylcarbamate (6.0 g, 66.0%) as an oil. at reflux for 20 hours the solvent was removed under reduced pressure The residue was dissolved in ethyl acetate (100 mL) washed with brine dried (sodium sulfate) filtered concentrated under reduced pressure The residue was purified by flash chromatography on silica gel (4:1 hexane/ethyl acetate)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1,1-dimethylethyl (3-bromo-2-fluorophenyl)carbamate (500 mg, 1.72 mmol) and 2,6-ditert-4-methylphenol (3 mg, 0.02 mmol) in toluene (3 mL) was deoxygenated for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (100 mg, 0.09 mmol) and tributyl(vinyl)tin (708 μl, 2.43 mmol) were added to the solution, which was then stirred at refluxed for 4 hrs. The mixture was cooled to room temperature, and then filtered through a pad of celite. The filtrate was concentrated in-vacuo to afford an orange residue, which was purified by column chromatography (silica gel, 5% ether in hexane). The product was isolated as a colorless oil, and was then diluted in dichloromethane (2 mL). To the solution was added trifluoroacetic acid (500 μl), and the solution was stirred at ambient temperature for 1 hour. The solution was partitioned between saturated sodium bicarbonate and dichloromethane. The aqueous portion was extracted twice with dichloromethane, and the combined organic portions were washed with brine, dried over sodium sulfate, filtered, and concentrated in-vacuo to afford 138 mg, 1.0 mmol, (58% over two steps) of 3-ethenyl-2-fluoroaniline as a colorless oil. 1H NMR (400 MHz, CDCl3): 6.92-6.82 (m, 3H), 6.71-6.66 (m, 1H), 5.80 (d, 1H), 5.35 (d, 1H); 3.72 (br s, 2H); MS (EI) for C8H8FN: 138 (MH+). at refluxed for 4 hrs filtered through a pad of celite The filtrate was concentrated in-vacuo to afford an orange residue, which was purified by column chromatography (silica gel, 5% ether in hexane) The product was isolated as a colorless oil the solution was stirred at ambient temperature for 1 hour The solution was partitioned between saturated sodium bicarbonate and dichloromethane The aqueous portion was extracted twice with dichloromethane the combined organic portions were washed with brine dried over sodium sulfate filtered concentrated in-vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1,1-dimethylethyl (3-bromo-2-fluorophenyl)carbamate (500 mg, 1.72 mmol) and 2,6-ditert-4-methylphenol (3 mg, 0.02 mmol) in toluene (3 mL) was deoxygenated for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (100 mg, 0.09 mmol) and tributyl(vinyl)tin (708 μl, 2.43 mmol) were added to the solution, which was then stirred at refluxed for 4 hrs. The mixture was cooled to room temperature, and then filtered through a pad of celite. The filtrate was concentrated in-vacuo to afford an orange residue, which was purified by column chromatography (silica gel, 5% ether in hexane). The product was isolated as a colorless oil, and was then diluted in dichloromethane (2 mL). To the solution was added trifluoroacetic acid (500 μl), and the solution was stirred at ambient temperature for 1 hour. The solution was partitioned between saturated sodium bicarbonate and dichloromethane. The aqueous portion was extracted twice with dichloromethane, and the combined organic portions were washed with brine, dried over sodium sulfate, filtered, and concentrated in-vacuo to afford 138 mg, 1.0 mmol, (58% over two steps) of 3-ethenyl-2-fluoroaniline as a colorless oil. 1H NMR (400 MHz, CDCl3): 6.92-6.82 (m, 3H), 6.71-6.66 (m, 1H), 5.80 (d, 1H), 5.35 (d, 1H); 3.72 (br s, 2H); MS (EI) for C8H8FN: 138 (MH+). at refluxed for 4 hrs filtered through a pad of celite The filtrate was concentrated in-vacuo to afford an orange residue, which was purified by column chromatography (silica gel, 5% ether in hexane) The product was isolated as a colorless oil the solution was stirred at ambient temperature for 1 hour The solution was partitioned between saturated sodium bicarbonate and dichloromethane The aqueous portion was extracted twice with dichloromethane the combined organic portions were washed with brine dried over sodium sulfate filtered concentrated in-vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1,1-dimethylethyl (3-bromo-2-fluorophenyl)carbamate (500 mg, 1.72 mmol) and 2,6-ditert-4-methylphenol (3 mg, 0.02 mmol) in toluene (3 mL) was deoxygenated for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (100 mg, 0.09 mmol) and tributyl(vinyl)tin (708 μl, 2.43 mmol) were added to the solution, which was then stirred at refluxed for 4 hrs. The mixture was cooled to room temperature, and then filtered through a pad of celite. The filtrate was concentrated in-vacuo to afford an orange residue, which was purified by column chromatography (silica gel, 5% ether in hexane). The product was isolated as a colorless oil, and was then diluted in dichloromethane (2 mL). To the solution was added trifluoroacetic acid (500 μl), and the solution was stirred at ambient temperature for 1 hour. The solution was partitioned between saturated sodium bicarbonate and dichloromethane. The aqueous portion was extracted twice with dichloromethane, and the combined organic portions were washed with brine, dried over sodium sulfate, filtered, and concentrated in-vacuo to afford 138 mg, 1.0 mmol, (58% over two steps) of 3-ethenyl-2-fluoroaniline as a colorless oil. 1H NMR (400 MHz, CDCl3): 6.92-6.82 (m, 3H), 6.71-6.66 (m, 1H), 5.80 (d, 1H), 5.35 (d, 1H); 3.72 (br s, 2H); MS (EI) for C8H8FN: 138 (MH+). at refluxed for 4 hrs filtered through a pad of celite The filtrate was concentrated in-vacuo to afford an orange residue, which was purified by column chromatography (silica gel, 5% ether in hexane) The product was isolated as a colorless oil the solution was stirred at ambient temperature for 1 hour The solution was partitioned between saturated sodium bicarbonate and dichloromethane The aqueous portion was extracted twice with dichloromethane the combined organic portions were washed with brine dried over sodium sulfate filtered concentrated in-vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: tert-Butyl 4-[(4-chloro-6-methoxyquinazolin-7-yl)oxy]piperidine-1-carboxylate was coupled with tert-butyl (3-bromo-2-fluorophenyl)carbamate using an analogous process to that described in Example 22 (preparation of starting materials) for the preparation of N-(3-chloro-4-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine hydrochloride, to give N-(3-bromo-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine hydrochloride; 1H NMR Spectrum: (DMSO d6) 1.85-2.1 (m, 2H), 2.1-2.32 (m, 2H), 3.0-3.35 (m, 4H), 4.02 (s, 3H), 4.83-5.0 (m, 1H), 7.3 (dd, 1H), 7.5-7.65 (m, 2H), 7.75 (dd, 1H), 8.45 (s, 1H), 8.8(s, 1H), 9.15 (bs, 2H), 11.86 (s, 1H); Mass Spectrum: (M+H)+ 447.12.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of tert-butyl (3-bromo-2-fluorophenyl)carbamate (7.23 g, 24.9 mmol) in EtOAc (125 mL) was added 4 M HCl/EtOAc (62 mL) at 0° C. The mixture was stirred at room temperature for 12 h and concentrated in vacuo. The residue was diluted with 6 M HCl aqueous solution (62 mL). To the suspension was added a solution of NaNO2 (2.06 g, 29.9 mmol) in water (5 mL) at 0° C. To a suspension of methyl 4-methoxy-3-oxobutanoate (3.22 mL, 24.9 mmol) and NaOAc (92.9 g) in EtOH (84 mL) was added the above mixture at 0° C. The mixture was stirred at 0° C. for 20 min. The precipitates were collected by filtration, diluted with EtOAc, washed with NaHCO3 aqueous solution, dried over MgSO4, filtered and concentrated in vacuo to yield the title compound (5.36 g, 62% yield) as a brown solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.30 (3H, s), 3.75-3.94 (3H, m), 4.56-4.71 (2H, m), 7.15-7.34 (1H, m), 7.37-7.59 (1H, m), 7.63-7.80 (1H, m), 12.26 (1H, s). concentrated in vacuo The residue was diluted with 6 M HCl aqueous solution (62 mL) was added the above mixture at 0° C The mixture was stirred at 0° C. for 20 min The precipitates were collected by filtration diluted with EtOAc washed with NaHCO3 aqueous solution dried over MgSO4 filtered concentrated in vacuo