(5-bromo-2-methoxyphenyl)boronic acid

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

実験手順: (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-bromo-5-fluorobenzyl)-4-methyl-1,3-oxazolidin-2-one (600 mg, 1.2 mmol), (5-bromo-2-methoxyphenyl)boronic acid (319 mg, 1.38 mmol), sodium carbonate aqueous solution (1.27 mL, 2M, 2.54 mmol), toluene (3.5 mL) and ethanol (400 μL) were mixed and stirred at room temperature for 45 minutes followed by addition of tetrakis(triphenylphosphine)palladium(0) (87 mg, 4.5 mol %). The resulting mixture was heated in a 90° C. oil bath for 24 hours to complete the reaction. The crude reaction was diluted with brine and extracted with ethyl acetate. The combined extracts were dried over Na2SO4 followed by filtration and concentration in vacuo to afford a dark oil. The crude oil was purified by reverse-phase preparative HPLC (Kromasil 100-5C18, 100×21.1 mm) eluting with a MeCN (0.1% TFA, v/v)/H2O (0.1% TFA, v/v) gradient mixture affording (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(5′-bromo-4-fluoro-2′-methoxybiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one. LCMS calc.=607.04; found=607.98 (M+1)+. The resulting mixture was heated in a 90° C. oil bath for 24 hours the reaction The crude reaction extracted with ethyl acetate The combined extracts were dried over Na2SO4 followed by filtration and concentration in vacuo to afford a dark oil The crude oil was purified by reverse-phase preparative HPLC (Kromasil 100-5C18, 100×21.1 mm) eluting with a MeCN (0.1% TFA, v/v)/H2O (0.1% TFA, v/v) gradient mixture

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

実験手順: (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-bromo-5-fluorobenzyl)-4-methyl-1,3-oxazolidin-2-one (600 mg, 1.2 mmol), (5-bromo-2-methoxyphenyl)boronic acid (319 mg, 1.38 mmol), sodium carbonate aqueous solution (1.27 mL, 2M, 2.54 mmol), toluene (3.5 mL) and ethanol (400 μL) were mixed and stirred at room temperature for 45 minutes followed by addition of tetrakis(triphenylphosphine)palladium(0) (87 mg, 4.5 mol %). The resulting mixture was heated in a 90° C. oil bath for 24 hours to complete the reaction. The crude reaction was diluted with brine and extracted with ethyl acetate. The combined extracts were dried over Na2SO4 followed by filtration and concentration in vacuo to afford a dark oil. The crude oil was purified by reverse-phase preparative HPLC (Kromasil 100-5C18, 100×21.1 mm) eluting with a MeCN (0.1% TFA, v/v)/H2O (0.1% TFA, v/v) gradient mixture affording (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(5′-bromo-4-fluoro-2′-methoxybiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one. LCMS calc.=607.04; found=607.98 (M+1)+. The resulting mixture was heated in a 90° C. oil bath for 24 hours the reaction The crude reaction extracted with ethyl acetate The combined extracts were dried over Na2SO4 followed by filtration and concentration in vacuo to afford a dark oil The crude oil was purified by reverse-phase preparative HPLC (Kromasil 100-5C18, 100×21.1 mm) eluting with a MeCN (0.1% TFA, v/v)/H2O (0.1% TFA, v/v) gradient mixture

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

実験手順: A mixture of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (6-80 g, 11.39 mmol), 2-methoxy-5-bromo-phenyl boronic acid (3.00 g, 12.99 mmol), and sodium carbonate (2.65 g, 25.0 mmol) in 200 ml of 1:2:4 mixture of water:EtOH:toluene was stirred at room temperature for 30 min. Catalytic amount of tetrakis(triphenylphosphine) palladium (0.66 g, 5% mol) was added. The mixture was stirred under reflux for 24 h. TLC (CH2Cl2:hexane/1:1) showed no starting material. The solvents were removed. Water (100 ml) was added. The mixture was extracted with methylene chloride (3×100 ml). The combined methylene chloride layers were washed with brine and dried over sodium sulfate. The title compound was obtained after flash column using CH2Cl2:hexane/6:4 as the eluant. 1H NMR (CDCl3, 500 MHz): δ 1:1 mixture of atropisomers 7.88 (s, 1H), 7.74 (s, 1H), 7.72 (s, 1H), 7.67 (t, J=7 Hz, 1H), 7.62 (s, 1H), 7.54 (m, 1H), 7.37-7.42 (m, 1H), 7.31-7.34 (m, 1H), 6.90-6.93 (m, 1H), 5.63 (d, J=8 Hz, 0.5H), 5.25 (d, J=8 Hz, 0.5H), 4.98 (d, J=15.5 Hz, 0.5H), 4.88 (d, J=16 Hz, 0.5H), 4.12 (d, J=15.5 Hz, 0.5H), 3.88 (d, J=16.5 Hz, 0.5H), 3.84 (s, 3H), 3.81 (s, 3H), 3.73 (m, 1H), 0.59 (d, J=6.5 Hz, 1.5H), 0.45 (d, J=6.5 Hz, 1.5H). under reflux for 24 h The solvents were removed Water (100 ml) was added The mixture was extracted with methylene chloride (3×100 ml) The combined methylene chloride layers were washed with brine dried over sodium sulfate

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

実験手順: A mixture of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (6-80 g, 11.39 mmol), 2-methoxy-5-bromo-phenyl boronic acid (3.00 g, 12.99 mmol), and sodium carbonate (2.65 g, 25.0 mmol) in 200 ml of 1:2:4 mixture of water:EtOH:toluene was stirred at room temperature for 30 min. Catalytic amount of tetrakis(triphenylphosphine) palladium (0.66 g, 5% mol) was added. The mixture was stirred under reflux for 24 h. TLC (CH2Cl2:hexane/1:1) showed no starting material. The solvents were removed. Water (100 ml) was added. The mixture was extracted with methylene chloride (3×100 ml). The combined methylene chloride layers were washed with brine and dried over sodium sulfate. The title compound was obtained after flash column using CH2Cl2:hexane/6:4 as the eluant. 1H NMR (CDCl3, 500 MHz): δ 1:1 mixture of atropisomers 7.88 (s, 1H), 7.74 (s, 1H), 7.72 (s, 1H), 7.67 (t, J=7 Hz, 1H), 7.62 (s, 1H), 7.54 (m, 1H), 7.37-7.42 (m, 1H), 7.31-7.34 (m, 1H), 6.90-6.93 (m, 1H), 5.63 (d, J=8 Hz, 0.5H), 5.25 (d, J=8 Hz, 0.5H), 4.98 (d, J=15.5 Hz, 0.5H), 4.88 (d, J=16 Hz, 0.5H), 4.12 (d, J=15.5 Hz, 0.5H), 3.88 (d, J=16.5 Hz, 0.5H), 3.84 (s, 3H), 3.81 (s, 3H), 3.73 (m, 1H), 0.59 (d, J=6.5 Hz, 1.5H), 0.45 (d, J=6.5 Hz, 1.5H). under reflux for 24 h The solvents were removed Water (100 ml) was added The mixture was extracted with methylene chloride (3×100 ml) The combined methylene chloride layers were washed with brine dried over sodium sulfate

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

実験手順: Following the method described in Example 4 for the synthesis of 4-chloro-6-(5-chloro-2-methoxy-phenyl)-pyrimidin-2-yl-amine, 4,6-dichloro-pyrimidin-2-yl-amine and 5-bromo-2-methoxy-phenyl boronic acid provided 4-chloro-6-(5-bromo-2-methoxy-phenyl)-pyrimidin-2-yl-amine (53% yield).

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

実験手順: Following the method described in Example 4 for the synthesis of 4-chloro-6-(5-chloro-2-methoxy-phenyl)-pyrimidin-2-yl-amine, 4,6-dichloro-pyrimidin-2-yl-amine and 5-bromo-2-methoxy-phenyl boronic acid provided 4-chloro-6-(5-bromo-2-methoxy-phenyl)-pyrimidin-2-yl-amine (53% yield).

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

実験手順: (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-bromo-5-fluorobenzyl)-4-methyl-1,3-oxazolidin-2-one (600 mg, 1.2 mmol), (5-bromo-2-methoxyphenyl)boronic acid (319 mg, 1.38 mmol), sodium carbonate aqueous solution (1.27 mL, 2M, 2.54 mmol), toluene (3.5 mL) and ethanol (400 μL) were mixed and stirred at room temperature for 45 minutes followed by addition of tetrakis(triphenylphosphine)palladium(0) (87 mg, 4.5 mol %). The resulting mixture was heated in a 90° C. oil bath for 24 hours to complete the reaction. The crude reaction was diluted with brine and extracted with ethyl acetate. The combined extracts were dried over Na2SO4 followed by filtration and concentration in vacuo to afford a dark oil. The crude oil was purified by reverse-phase preparative HPLC (Kromasil 100-5C18, 100×21.1 mm) eluting with a MeCN (0.1% TFA, v/v)/H2O (0.1% TFA, v/v) gradient mixtureaffording (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(5′-bromo-4-fluoro-2′-methoxybiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one. LCMS calc.=607.04; found=607.98 (M+1)+. The resulting mixture was heated in a 90° C. oil bath for 24 hours the reaction The crude reaction extracted with ethyl acetate The combined extracts were dried over Na2SO4 followed by filtration and concentration in vacuo to afford a dark oil The crude oil was purified by reverse-phase preparative HPLC (Kromasil 100-5C18, 100×21.1 mm) eluting with a MeCN (0.1% TFA, v/v)/H2O (0.1% TFA, v/v) gradient

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

実験手順: A mixture of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (6.80 g, 11.39 mmol), 2-methoxy-5-bromo-phenyl boronic acid (3.00 g, 12.99 mmol), and sodium carbonate (2.65 g, 25.0 mmol) in 200 ml of 1:2:4 mixture of water:EtOH:toluene was stirred at room temperature for 30 min. Catalytic amount of tetrakis(triphenylphosphine) palladium (0.66 g, 5% mol) was added. The mixture was stirred under reflux for 24 h. TLC (CH2Cl2:hexane/1:1) showed no starting material. The solvents were removed. Water (100 ml) was added. The mixture was extracted with methylene chloride (3×100 ml). The combined methylene chloride layers were washed with brine and dried over sodium sulfate. The title compound was obtained after flash column using CH2Cl2:hexane/6:4 as the eluant. 1H NMR (CDCl3, 500 MHz): δ 1:1 mixture of atropisomers 7.88 (s, 1H), 7.74 (s, 1H), 7.72 (s, 1H), 7.67 (t, J=7 Hz, 1H), 7.62 (s, 1H), 7.54 (m, 1H), 7.31-7.34 (m, 1H), 6.90-6.93 (m, 1H), 5.63 (d, J=8 Hz, 0.5H), 5.25 (d, J=8 Hz, 0.5H), 4.98 (d, J=15.5 Hz, 0.5H), 4.88 (d, J=16 Hz, 0.5H), 4.12 (d, J=15.5 Hz, 0.5H), 3.88 (d, J=16.5 Hz, 0.5H), 3.84 (s, 3H), 3.81 (s, 3H), 3.73 (m, 1H), 0.59 (d, J=6.5 Hz, 1.5H), 0.45 (d, J=6.5 Hz, 1.5H). under reflux for 24 h The solvents were removed Water (100 ml) was added The mixture was extracted with methylene chloride (3×100 ml) The combined methylene chloride layers were washed with brine dried over sodium sulfate

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

実験手順: I-208 was synthesized from 5-bromo-2-methoxyphenylboronic acid (2.00 g, 8.66 mmol) and 3-chloroiodobenzene (2.48 g, 10.4 mmol) using the same conditions as for I-207. The reaction time was extended to 16 h. The methanol was removed under vacuum, and the residue dissolved in ethyl acetate (100 mL), washed with water (100 mL), and the aqueous wash extracted with ethyl acetate (100 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (2×200 mL), water (2×200 mL) and brine (150 mL), dried over sodium sulfate, filtered and the solvent removed under vacuum to give I-208 (2.56 g, 99% yield). 1H NMR (400 MHz, CDCl3) 7.49-7.48 (m, 1H), 7.44-7.40 (m, 2H), 7.36-7.31 (m, 3H), 6.85 (d, J=8.4 Hz, 1H), 3.80 (s, 3H) ppm. The methanol was removed under vacuum the residue dissolved in ethyl acetate (100 mL) washed with water (100 mL) the aqueous wash extracted with ethyl acetate (100 mL) The combined organic extracts were washed with saturated aqueous sodium bicarbonate (2×200 mL), water (2×200 mL) and brine (150 mL) dried over sodium sulfate filtered the solvent removed under vacuum to give I-208 (2.56 g, 99% yield)

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

実験手順: A suspension of 5-bromo-2-methoxyphenylboronic acid (500 mg, 2.17 mmol), 3-iodonitrobenzene (647 mg, 2.60 mmol), and potassium carbonate (599 mg, 4.33 mmol) in methanol (10 mL) and water (2 mL) was degassed for 30 min under a nitrogen stream followed by the addition of palladium(II) acetate (9.72 mg, 0.0433 mmol). The reaction was stirred at room temperature for 4 h. The methanol was removed under reduced pressure, ethyl acetate (50 mL) and water (50 mL) were added, and the biphasic suspension was filtered. The layers were separated and the organic was washed with water (50 mL). The aqueous washes were combined and extracted with ethyl acetate (2×50 mL), and the organic extracts combined. The organic solution was washed with water (3×50 mL), saturated aqueous sodium bicarbonate (50 mL), brine, dried over sodium sulfate, filtered, and the solvent removed under vacuum to give a crude brown gum. The product was purified by flash silica gel column chromatography (5% ethyl acetate in hexanes), and crystallized by dissolving in diethyl ether (20 mL) and hexanes (50 mL), removing one half of the solvent under vacuum, filtering and washing with hexanes (2×10 mL) to give I-207 (417.8 mg, 63% yield). 1H NMR (400 MHz, CDCl3) 8.38 (t, J=1.8 Hz, 1H), 8.21-8.19 (m, 1H), 7.81 (dt, J=7.5 Hz, 1.3 Hz, 1H), 7.58 (t, J=8.0 Hz, 1H), 7.50-7.45 (m, 2H), 6.90 (d, J=8.8 Hz, 1H), 3.82 (s, 3H) ppm. was degassed for 30 min under a nitrogen stream The methanol was removed under reduced pressure, ethyl acetate (50 mL) and water (50 mL) were added the biphasic suspension was filtered The layers were separated the organic was washed with water (50 mL) extracted with ethyl acetate (2×50 mL) The organic solution was washed with water (3×50 mL), saturated aqueous sodium bicarbonate (50 mL), brine dried over sodium sulfate filtered the solvent removed under vacuum to give a crude brown gum The product was purified by flash silica gel column chromatography (5% ethyl acetate in hexanes) crystallized by dissolving in diethyl ether (20 mL) hexanes (50 mL), removing one half of the solvent under vacuum filtering washing with hexanes (2×10 mL) to give I-207 (417.8 mg, 63% yield)

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

実験手順: (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-bromo-5-fluorobenzyl)-4-methyl-1,3-oxazolidin-2-one (600 mg, 1.2 mmol), (5-bromo-2-methoxyphenyl)boronic acid (319 mg, 1.38 mmol), sodium carbonate aqueous solution (1.27 mL, 2M, 2.54 mmol), toluene (3.5 mL) and ethanol (400 μL) were mixed and stirred at room temperature for 45 minutes followed by addition of tetrakis(triphenylphosphine)palladium(0) (87 mg, 4.5 mol %). The resulting mixture was heated in a 90° C. oil bath for 24 hours to complete the reaction. The crude reaction was diluted with brine and extracted with ethyl acetate. The combined extracts were dried over Na2SO4 followed by filtration and concentration in vacuo to afford a dark oil. The crude oil was purified by reverse-phase preparative HPLC (Kromasil 100-5C18, 100×21.1 mm) eluting with a MeCN (0.1% TFA, v/v)/H2O (0.1% TFA, v/v) gradient mixture affording (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(5′-bromo-4-fluoro-2′-methoxybiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one. LCMS calc.=607.04; found=607.98 (M+1)+. The resulting mixture was heated in a 90° C. oil bath for 24 hours the reaction The crude reaction extracted with ethyl acetate The combined extracts were dried over Na2SO4 followed by filtration and concentration in vacuo to afford a dark oil The crude oil was purified by reverse-phase preparative HPLC (Kromasil 100-5C18, 100×21.1 mm) eluting with a MeCN (0.1% TFA, v/v)/H2O (0.1% TFA, v/v) gradient mixture

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

実験手順: A mixture of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (6-80 g, 11.39 mmol), 2-methoxy-5-bromo-phenyl boronic acid (3.00 g, 12.99 mmol), and sodium carbonate (2.65 g, 25.0 mmol) in 200 ml of 1:2:4 mixture of water:EtOH:toluene was stirred at room temperature for 30 min. Catalytic amount of tetrakis(triphenylphosphine) palladium (0.66 g, 5% mol) was added. The mixture was stirred under reflux for 24 h. TLC (CH2Cl2:hexane/1:1) showed no starting material. The solvents were removed. Water (100 ml) was added. The mixture was extracted with methylene chloride (3×100 ml). The combined methylene chloride layers were washed with brine and dried over sodium sulfate. The title compound was obtained after flash column using CH2Cl2:hexane/6:4 as the eluant. 1H NMR (CDCl3, 500 MHz): δ 1:1 mixture of atropisomers 7.88 (s, 1H), 7.74 (s, 1H), 7.72 (s, 1H), 7.67 (t, J=7 Hz, 1H), 7.62 (s, 1H), 7.54 (m, 1H), 7.37-7.42 (m, 1H), 7.31-7.34 (m, 1H), 6.90-6.93 (m, 1H), 5.63 (d, J=8 Hz, 0.5H), 5.25 (d, J=8 Hz, 0.5H), 4.98 (d, J=15.5 Hz, 0.5H), 4.88 (d, J=16 Hz, 0.5H), 4.12 (d, J=15.5 Hz, 0.5H), 3.88 (d, J=16.5 Hz, 0.5H), 3.84 (s, 3H), 3.81 (s, 3H), 3.73 (m, 1H), 0.59 (d, J=6.5 Hz, 1.5H), 0.45 (d, J=6.5 Hz, 1.5H). under reflux for 24 h The solvents were removed Water (100 ml) was added The mixture was extracted with methylene chloride (3×100 ml) The combined methylene chloride layers were washed with brine dried over sodium sulfate