1-bromo-3-fluoro-2-methoxybenzene

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: n-BuLi (17.0 mL, 42.5 mmol) was added dropwise to the solution of NH(i-Pr)2 (4.50 g, 44.5 mmol) in 70 mL of THF at −70° C. The mixture was stirred at 0° C. for 15 minutes and then cooled to −70° C. again. The solution of 1-bromo-3-fluoro-2-methoxybenzene (8.30 g, 40.5 mmol, in 30 mL of THF) was added dropwise. The resulting mixture was stirred at −70° C. for 1 hour then poured into fresh dry ice and stirred overnight. The mixture was diluted with 1 L of ether and washed with water twice. The combined water layer was washed with ether then acidified to pH=2 with hydrochloric acid and extracted with EtOAc twice. The combined EtOAc layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to give 4-bromo-2-fluoro-3-methoxybenzoic acid. cooled to −70° C. again The resulting mixture was stirred at −70° C. for 1 hour stirred overnight washed with water twice The combined water layer was washed with ether extracted with EtOAc twice The combined EtOAc layer was washed with brine dried over anhydrous Na2SO4 concentrated

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: NaNO2 (12.0 g, 173 mmol, in 40 mL of water) solution was added dropwise to the mixture of 3-fluoro-2-methoxyaniline (20.0 g, 158 mmol) in 200 mL of hydrobromic acid (47%) and 100 mL of water at −5˜0° C. and stirred for 1 hour. This solution was then added slowly to the suspension of CuBr (45.2 g, 315 mmol) in 50 mL of hydrobromic acid (47%) at 0° C. The resulting mixture was stirred at 0° C. for 1 hour then warmed to 50° C. and stirred for 1 hour. The reaction mixture was poured into ice water and extracted with ether (2×500 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to give 1-bromo-3-fluoro-2-methoxybenzene. The resulting mixture was stirred at 0° C. for 1 hour stirred for 1 hour extracted with ether (2×500 mL) The combined organic layer was washed with brine dried over anhydrous Na2SO4 concentrated

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Lithium diisopropylamide (LDA) is formed by dropwise addition of n-butyllithium (1.6 M in hexanes, 56.0 mL, 89.6 mmol) to a stirred solution of diisopropylamine (13.7 mL, 96.9 mmol) in tetrahydrofuran (150 mL) at −78° C. The resulting solution is stirred at −78° C. for 5 min, 0° C. for 15 min, and then cooled again to −78° C. A solution of 1-bromo-3-fluoro-2-methoxybenzene (15.28 g, 74.5 mmol) in tetrahydrofuran (40 mL) is added dropwise to the previous solution over a period of 30 min. to give an amber solution. After stirring this solution at −78° C. for 1.5 h, dry ice (˜125 g) is added, and the resulting mixture is allowed to warm slowly (˜1 h) to room temperature with stirring as it degasses. The reaction mixture is acidified to pH ˜1 by addition of a 5% aqueous solution of hydrochloric acid (˜500 mL), and the product is extracted with diethyl ether (6×100 mL). The combined organic extracts are washed with brine (100 mL), and the product extracted with a saturated solution of aqueous sodium bicarbonate (3×100 mL). The combined aqueous extracts (pH ˜9) are washed with diethyl ether (3×100 mL) and acidified slowly to pH ˜1 by addition of a 37% aqueous solution of hydrochloric acid (˜50 mL). The product is extracted with diethyl ether (3×200 mL), and the combined organic extracts are washed with brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 12 as an off-white solid. This product is of sufficient purity (≧95% by NMR spectroscopy) to use directly in the next synthetic step. mp 168-170° C. 1H NMR (CD3OD): δ 3.92 (d, JH-F=1.0 Hz, 3H, OCH3), 7.44 (dd, JH-H=8.5 Hz, JH-F=1.5 Hz, 1H, H-5), 7.55 (dd, JH-H=8.5 Hz, JH-F=7.0 Hz, 1H, H-6). 19F{1H} NMR (CD3OD): δ −127.0 (s). 13C{1H} NMR (CD3OD): 662.1 (d, JC-F=4.5 Hz, OCH3), 121.5 (d, JC-F=8.5 Hz, C-1), 123.6 (d, JC-F=2.0 Hz, C-4), 128.0 (s, C-6), 129.0 (d, JC-F=4.5 Hz, C-5), 147.7 (d, JC-F=13.5 Hz, C-3), 157.1 (d, JC-F=263.5 Hz, C-2), 166.3 (d, JC-F=3.0 Hz, CO2H). HRMS m/z calcd for C8H679BrFNaO3 270.9382 ([M+Na]+). Found 270.9377. cooled again to −78° C to give an amber solution After stirring this solution at −78° C. for 1.5 h to warm slowly (˜1 h) to room temperature with stirring as it the product is extracted with diethyl ether (6×100 mL) The combined organic extracts are washed with brine (100 mL) the product extracted with a saturated solution of aqueous sodium bicarbonate (3×100 mL) The combined aqueous extracts (pH ˜9) are washed with diethyl ether (3×100 mL) acidified slowly to pH ˜1 by addition of a 37% aqueous solution of hydrochloric acid (˜50 mL) The product is extracted with diethyl ether (3×200 mL) the combined organic extracts are washed with brine (100 mL) dried over anhydrous magnesium sulfate concentrated under reduced pressure

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Hydrobromic acid (48% in water, 140 mL) is added slowly to an aliquot of 11 (14.33 g, 101.5 mmol) cooled to 0° C. The resulting solid is broken up with a glass rod and stirred vigorously at 0° C. for 10 min. A solution of sodium nitrite (7.40 g, 107.2 mmol) in water (50 mL) is added slowly (˜1.5 h) to the stirred slurry containing 3-fluoro-2-methoxyphenylamine and hydrobromic acid, maintaining the temperature of the reaction mixture below 5° C. A purple solution of cuprous bromide (9.62 g, 67.1 mmol) in hydrobromic acid (48% in water, 50 mL) is added dropwise to the reaction mixture, maintaining the temperature of the reaction mixture below 5° C. The resulting reaction mixture is heated at 60° C. until the evolution of gas ceases (˜2.5 h). The reaction mixture is cooled to room temperature, and the product extracted with diethyl ether (6×150 mL). The combined organic extracts are washed with brine (3×150 mL), dried over magnesium sulfate, and evaporated under reduced pressure to give 1-bromo-3-fluoro-2-methoxybenzene as a brown oil. This product is of sufficient purity (≧95% by NMR spectroscopy) to use directly in the next synthetic step. 1H NMR (CDCl3): δ 3.95 (d, JH-F=1.5 Hz, 3H, OCH3), 6.88 (apparent t of d, JH-H=8.0 Hz, JH-F=5.5 Hz, 1H, H-5), 7.04 (d, JH-F=10.5 Hz, JH-H=8.0 Hz, JH-H=1.5 Hz, 1H, H-4), 7.30 (d of apparent t, JH-H=8.0 Hz, JH-H=1.5 Hz, JH-F=1.5 Hz, 1H, H-6). 19F{1H} NMR (CDCl3): δ −127.7 (s). 13C{1H} NMR (CDCl3): δ 61.4 (d, JC-F=5.0 Hz, OCH3), 116.2 (d, JC-F=19.5 Hz, C-4), 117.7 (d, JC-F=3.0 Hz, C-1), 124.5 (d, JC-F=8.0 Hz, C-5), 128.5 (d, JC-F=3.5 Hz, C-6), 145.7 (d, JC-F=12.5 Hz, C-2), 156.2 (d, JC-F=250.5 Hz, C-3). maintaining the temperature of the reaction mixture below 5° C maintaining the temperature of the reaction mixture below 5° C The resulting reaction mixture is heated at 60° C. until the evolution of gas ceases (˜2.5 h) The reaction mixture is cooled to room temperature the product extracted with diethyl ether (6×150 mL) The combined organic extracts are washed with brine (3×150 mL) dried over magnesium sulfate evaporated under reduced pressure

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a 3-L round-bottom flask were added a stire bar, 2-bromo-6-fluoroanisol (75.00 g, 370 mmol) and dry THF (1460 mL). The flask was purged with nitrogen and cooled to 0° Celsius before adding 2.0 M i-PrMgCl in THF (408 mL, 916 mmol) over the course of 15 min. The resultant mixture was stirred for 2 hours before adding cyclobutanone (34 mL, 455 mmol). The resultant mixture was stirred for 0.5 hour before diluting with Et2O (2.50 L) and washing with saturated NH4Cl followed by brine. The organic layer was isolated, dried over MgSO4, filtered and concentrated to dryness to give the crude product. Subjecting the residue to FCC gave the title compound (55.58 g). 1H NMR (400 MHz, CDCl3) δ 6.98-6.88 (m, 3H), 3.90-3.90 (s, 3H), 2.46-2.42 (m, 2H), 2.31-2.28 (m, 2H), 2.04 (m, 1H), 1.67-1.64 (m, 1H). To a 3-L round-bottom flask were added a stire bar The flask was purged with nitrogen washing with saturated NH4Cl The organic layer was isolated dried over MgSO4 filtered concentrated to dryness to give the crude product

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a 500 mL round-bottomed flask were added a stir bar, 2-bromo-6-fluoroanisol (11.03 g, 53.8 mmol) and dry THF (215 mL). The flask was purged with nitrogen and cooled to 0° Celsius before adding 2.0 M i-PrMgCl in THF (60 mL, 120 mmol) over the course of 3 min. The resultant mixture was stirred for 2 h before adding cyclobutanone (5.0 mL, 67 mmol). The resultant mixture was stirred for 0.5 hour before diluting with Et2O (500 mL) and washing with saturated NH4Cl followed by brine. The organic layer was isolated, dried over MgSO4, filtered and concentrated to dryness to give a pale-yellow oil. Subjecting the residue to FCC yielded 1-(3-fluoro-2-methoxyphenyl)cyclobutanol as a pale-yellow oil (5.18 g, 49%). 1H NMR (600 MHz, CDCl3) δ 7.07-7.03 (m, 1H), 7.03-6.98 (m, 1H), 6.98-6.94 (m, 1H), 3.99 (d, J=2.4, 3H), 3.39 (s, 1H), 2.57-2.45 (m, 2H), 2.41-2.31 (m, 2H), 2.17-2.05 (m, 1H), 1.75-1.65 (m, 1H). To a 500 mL round-bottomed flask were added a stir bar The flask was purged with nitrogen washing with saturated NH4Cl The organic layer was isolated dried over MgSO4 filtered concentrated to dryness to give a pale-yellow oil