5-Bromo-2-fluorophenol

Colorless to light yellow liquid

A cooled [(-20°C)] solution of 2, 2, 6, [6-TETRAMETHYLPIPERIDINE] (28 ml, 165 mmol) in tetrahydrofuran (400 ml) was treated with n-butyllithium (63 ml of a 2.5M solution in hexanes, 157.5 mmol). This mixture was then cooled [TO-78°C.] [1-BROMO-4-FLUOROBENZENE] (16.5 ml, 150 mmol) was then added neat and dropwise over 10 min and stirring [AT-78°C] was continued for 3 h. Triisopropyl borate (40 ml, 172. [5] mmol) was then added and stirring at-78°C continued for 30 min before removing the cooling bath. When the internal temperature of the reaction [REACHED-4°C, ] 5N hydrochloric acid (75 ml) was added and the mixture was stirred to ambient temperature. After stirring at ambient temp for 1 h the majority of the tetrahydrofuran was removed and the mixture partitioned between ether (500 ml) and IN hydrochloric acid (500 ml). The organics were then extracted with 2N sodium hydroxide (400 ml) and the organics were discarded. The aqueous was cooled in an ice-water bath and 5N hydrochloric acid (150 ml) was added dropwise over 15 min. The resulting white solid was collected and dried under vacuum to afford 5-bromo-2- fluorobenzeneboronic acid (25 g, 76percent). A solution of 5-bromo-2-fluorobenzeneboronic acid (25 g, 114 mmol) in tetrahydrofuran was treated with hydrogen peroxide (7. [8] ml of a [35] wt percent solution in water) then with sodium hydroxide (1.4 ml of a 4N solution in water). A mild exotherm caused the internal temperature to reach [40°C.] This mixture was left to stir at ambient temperature for 14 h then treated with manganese dioxide (200 mg) and stirring was continued for 90 min before filtering the reaction (GF/A filter paper). The filtrate was concentrated on a rotary evaporator and the residue partitioned between ether (400 ml) and water. The organics were washed with more water and brine, and dried over anhydrous magnesium sulphate. Filtration and evaporation to dryness afforded 5-bromo-2-fluorophenol (19.7 g, 90percent) as a colourless liquid : 8H (400 MHz, [DS-DMSO)] 6.93-6. 97 [(1H, ] m), 7.09-7. 14 (2H, m), 10.36 [(1H, ] br). An ice-cooled solution of 5-bromo-2-fluorophenol (1.91 g, 10 mmol), [(L-METHYL-LH-[1, ] 2, 3] triazol-4-yl) methanol (1.24 g, 11 mmol) and triphenylphosphine (3.93 g, 15 mmol) in tetrahydrofuran [(50] ml) was treated dropwise with diisopropyl azodicarboxylate (3.03 g, 15 mmol) over 10 min. The resulting mixture was stirred to ambient temperature over 12 h and then glacial acetic acid [(1] ml) was added. The reaction mixture was concentrated in vacuo then partitioned between ethyl acetate and 0. 01N sodium hydroxide solution. The organics were washed with water, brine, dried over anhydrous magnesium sulphate and concentrated to give an oil This oil was purified by chromatography on silica gel, eluting with isohexane on a gradient of ethyl acetate (20-50percent). Product-containing fractions were concentrated and the resulting residue triturated with 10percent ether in isohexane to furnish [4- (5-BROMO-2-FLUOROPHENOXYMETHYL)-L-] [METHYL-LH-[1, ] 2, 3] triazole as a white solid (1.9 g, 66percent): [8H (360] MHz, [D6-] DMSO) 4.06 (3H, s), 5.25 (2H, s), 7.10-7. 20 (2H, m), 7.55-7. 70 [(1H, ] m), 8.19 [(1H, ] s). 2- (8-Fluoroimidazo [1, 2-a] pyridin-7-yl) propan-2-ol was coupled to 4- [(5-BROMO-2-FLUOROPHENOXYMETHYL)-L-METHYL-LH-] [1, 2, 3] triazole as described in Example 6 to give [2- {8-FLUORO-3- [4-FLUORO-3- (1-METHYL-LH [1, ] 2, 3] triazol-4- ylmethoxy) phenyl] imidazo [1, 2-a] [PYRIDIN-7-YL} PROPAN-2-OL] as an off-white solid: [5H] (400 MHz, [D6-DMSO)] 1.58 (6H, s), 4.07 (3H, s), 5.35 (2H, s), 5.55 [(1H, ] s), 7.16-7. 23 (2H, m), 7.37 [(1H, ] dd, J 11 and 9), 7.65 [(1H, ] dd, J 8 and 2), 7.76 [(1H, ] s), 8.21 [(1H, ] s), 8. 43 [(1H, ] d, [J 7)] ; [MILZ] (ES+) 400 [MH+].A solution of the above product (25 g, 114 mmol) in tetrahydrofuran was treated with hydrogen peroxide (7.8 ml of a 35 wt percent solution in water) then with sodium hydroxide (1.4 ml of a 4N solution in water). A mild exotherm caused the internal temperature to reach 40°C. This mixture was left to stir at ambient temperature for 14 h then treated with manganese dioxide (200 mg) and stirring was continued for 90 min before filtering the reaction (GF/A filter paper). The filtrate was concentrated on a rotary evaporator and the residue partitioned between ether (400 ml) and water. The organics were washed with more water, brine and dried over anhydrous magnesium sulphate. Filtration and evaporation to dryness afforded 5-bromo-2-fluorophenol (19. 7 g, 90percent) as a colourless liquid:To a solution of 2, 2, 6, 6-tetramethyl piperidine (5.6 mL, 33.2 mmol) in THF at -20° C. was added n-BuLi (1.6 M in hexanes, 18.8 mL, 30 mmol). The mixture was stirred at -20° C. for 10 min before it was cooled to -78° C. 1-Bromo-4-fluorobenzene (2.95 mL, 27 mmol) was added over 10 min and the mixture was stirred at -78° C. for 2.0 h before trimethyl borate (6.0 mL, 54 mmol) was added. The mixture was stirred at -78° C. for 30 min and then at rt for 2.0 h. After it was cooled back to 0° C., glacial acetic acid (4.86 mL, 81 mmol) was added and stirred for 30 min, followed by addition of 30percent HTo a solution of 2, 2, 6, 6-tetramethyl piperidine (5.6 mL, 33.2 mmol) in THF at -20° C. was added n-BuLi (1.6 M in hexanes, 18.8 mL, 30 mmol). The mixture was stirred at -20° C. for 10 min before it was cooled to -78° C. 1-Bromo-4-flurobenzene (2.95 mL, 27 mmol) was added over 10 min and the mixture was stirred at -78° C. for 2.0 h before trimethyl borate (6.0 mL, 54 mmol) was added. The mixture was stirred at -78° C. for 30 min and then at rt for 2.0 h. After it was cooled back to 0° C., glacial acetic acid (4.86 mL, 81 mmol) was added and stirred for 30 min, followed by addition of 30percent HTo a stirred solution OF 4-BROMO-1-FLUORO-2-METHOXYBENZENE (1.00 g, 4.88 mmol) in anhydrous CH2CL2 (20 ml) was added dropwise in an ice bath BBR3 (1 M solution in CH2Cl2, 9.75 ml, 9. 75 mmol), and the mixture was stirred at room temperature overnight. The reaction was cooled in an ice bath and quenched by adding MEOH (1.0 ml) dropwise. The solvent was evaporated and the residue purified by flash chromatography eluting with ISOHEXANE/CH2CL2/MEOH (70: 20: 10) to leave 0.802 g (86percent) of the title compound: BH (400 MHz, CDCL3) 5.24 (1 H, s), 6.96 (2 H, m), 7.16 (1 H, DD, J7. 7, 2. 0 HZ).

Molecular Weight:191.00
XLogP3:2.4
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Exact Mass:189.94296
Monoisotopic Mass:189.94296
Topological Polar Surface Area:20.2
Heavy Atom Count:9
Complexity:99.1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes