(4-chloro-2-methoxyphenyl)boronic acid

反応条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-Chloropyridine-N-oxide (500 mg, 3.85 mmol), 2-methoxy-4-chlorophenylboronic acid (862 mg, 4.63 mmol) and K2CO3 (1.59 g, 11.55 mmol) were suspended in DMSO (5 mL) and PdCl2(dppf) (314 mg, 0.385 mmol) was added. The reaction mixture was placed under vacuum for 20 min and flushed with N2. This process was repeated, and the reaction mixture was heated at 120° C. for 3 h. The reaction mixture was cooled to 25° C. and partitioned between methylene chloride and 5% lithium chloride. The aqueous phase was removed, and the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. Flash chromatography (ISCO 40 g column, methylene chloride/MeOH 100:0 to 90:10) provided the title compound (673 mg, 74%) as a tan solid: 1H NMR (300 MHz, CD3OD) δ 8.21 (dd, J=5.4, 1.8 Hz, 2H), 7.47 (dd, J=5.6, 1.6 Hz, 2H), 7.26 (d, J=8.2 Hz, 1H), 7.06 (dd, J=8.3, 2.4 Hz, 1H), 7.00 (d, J=1.7 Hz, 1H), 3.87 (s, 3H); ESI MS m/z 235 [M+H]. flushed with N2 The reaction mixture was cooled to 25° C. partitioned between methylene chloride and 5% lithium chloride The aqueous phase was removed the organic phase was washed with brine dried over Na2SO4 filtered concentrated to dryness under reduced pressure

反応条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-Chloropyridine-N-oxide (500 mg, 3.85 mmol), 2-methoxy-4-chlorophenylboronic acid (862 mg, 4.63 mmol) and K2CO3 (1.59 g, 11.55 mmol) were suspended in DMSO (5 mL) and PdCl2(dppf) (314 mg, 0.385 mmol) was added. The reaction mixture was placed under vacuum for 20 min and flushed with N2. This process was repeated, and the reaction mixture was heated at 120° C. for 3 h. The reaction mixture was cooled to 25° C. and partitioned between methylene chloride and 5% lithium chloride. The aqueous phase was removed, and the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. Flash chromatography (ISCO 40 g column, methylene chloride/MeOH 100:0 to 90:10) provided the title compound (673 mg, 74%) as a tan solid: 1H NMR (300 MHz, CD3OD) δ 8.21 (dd, J=5.4, 1.8 Hz, 2H), 7.47 (dd, J=5.6, 1.6 Hz, 2H), 7.26 (d, J=8.2 Hz, 1H), 7.06 (dd, J=8.3, 2.4 Hz, 1H), 7.00 (d, J=1.7 Hz, 1H), 3.87 (s, 3H); ESI MS m/z 235 [M+H]+. flushed with N2 The reaction mixture was cooled to 25° C. partitioned between methylene chloride and 5% lithium chloride The aqueous phase was removed the organic phase was washed with brine dried over Na2SO4 filtered concentrated to dryness under reduced pressure

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Under argon, 250 mg (0.73 mmol) of the compound from Example 146A and 190 mg (1.07 mmol) of 4-chloro-2-methoxyphenylboronic acid are dissolved in 7 ml degassed DMF. A previously degassed solution of sodium carbonate (2 N in water, 1.09 ml, 2.18 mmol) and 42 mg of tetrakis(triphenylphosphine)palladium (0.036 mmol) are added. The resulting mixture is heated and stirred for 8 hrs at 90° C. After cooling to RT it is acidified with 10% hydrochloric acid and the mixture filtered. The filtrate is purified by preparative HPLC (Method 20). 159 mg (54% of theory) of the title compound and 54 mg (18% of theory) of the corresponding acid formed by hydrolysis (see also Example 148A) are obtained. degassed DMF The resulting mixture is heated After cooling to RT it the mixture filtered The filtrate is purified by preparative HPLC (Method 20)

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Under argon, 250 mg (0.73 mmol) of the compound from Example 146A and 190 mg (1.07 mmol) of 4-chloro-2-methoxyphenylboronic acid are dissolved in 7 ml degassed DMF. A previously degassed solution of sodium carbonate (2 N in water, 1.09 ml, 2.18 mmol) and 42 mg of tetrakis(triphenylphosphine)palladium (0.036 mmol) are added. The resulting mixture is heated and stirred for 8 hrs at 90° C. After cooling to RT it is acidified with 10% hydrochloric acid and the mixture filtered. The filtrate is purified by preparative HPLC (Method 20). 159 mg (54% of theory) of the title compound and 54 mg (18% of theory) of the corresponding acid formed by hydrolysis (see also Example 148A) are obtained. degassed DMF The resulting mixture is heated After cooling to RT it the mixture filtered The filtrate is purified by preparative HPLC (Method 20)

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Nitrogen was bubbled through a stirred solution of 5-bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine [Intermediate 4] (1 g, 3.00 mmol) and (4-chloro-2-methoxyphenyl)boronic acid (0.615 g, 3.30 mmol) in dioxane (20 mL). To this mixture was added Pd(PPh3)4 (0.173 g, 0.150 mmol) followed by a solution of Na2CO3 (0.954 g, 9.00 mmol) in water (5 mL). The reaction was heated at 80° C. for 18 hours. The reaction mixture was cooled to RT, diluted with EtOAc (150 mL) and washed with water (100 mL). The organic phase was separated, dried over MgSO4, and filtered. The filtrate was concentrated in vacuo to afford the crude product as a dark red/brown oil which solidified on standing. The crude material was purified by flash chromatography using an 80 g silica cartridge running a gradient of [2M NH3 in MeOH]/DCM to afford the title compound as an off-white solid (1.051 g, 89% yield). LC-MS: Rt 1.04 min; MS m/z 395.2 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.09 (d, J=8.59 Hz, 1H), 7.32 (d, J=2.02 Hz, 1H), 7.15 (dd, J=8.59, 2.02 Hz, 1H), 4.35 (tt, J=12.38, 3.54 Hz, 1H), 3.97 (s, 3H), 2.98 (s, 3H), 1.60 (dd, J=11.87, 3.28 Hz, 2H), 1.41 (t, J=12.13 Hz, 2H), 1.27 (s, 1H), 1.21 (s, 6H), 1.08 (s, 6H). The reaction mixture was cooled to RT washed with water (100 mL) The organic phase was separated dried over MgSO4 filtered The filtrate was concentrated in vacuo to afford the crude product as a dark red/brown oil which The crude material was purified by flash chromatography

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

実験手順: Followed the procedure described in General Scheme II, with modification. Step 1 was followed where the starting material was N-(4-(4-bromo-2-formylthiophen-3-yl)-3-methylphenyl)methanesulfonamide (Intermediate 4) instead of 3,4-dibromothiophene-2-carbaldehyde (Intermediate I), starting material 8A was 4-chloro-2-methoxyphenylboronic acid. After purification by column chromatography (PE:EtOAc=3:1) N-(4-(4-(4-chloro-2-methoxyphenyl)-2-formylthiophen-3-yl)-3-methylphenyl)methanesulfonamide (380 mg, yield 365.2%) was obtained. Step 3 of Scheme II was then followed with column conditions (PE: EtOAc=3:1) to afford (E)-ethyl 3-(4-(4-chloro-2-methoxyphenyl)-3-(2-methyl-4-(methylsulfonamido)phenyl)thiophen-2-yl)acrylate (280 mg, yield 63.4%). Step 4 of Scheme II gave 200 mg of product (yield 71%) followed by Step 5 (with purification by prep-HPLC) gave Example 10 (41.9 mg, 13% yield). 1H NMR (DMSO-d6 400 MHz): δ 9.73 (s, 1H), 7.38 (s, 1H), 6.93 (m, 4H), 6.90 (s, 1H), 6.86 (m, 1H), 3.5 (d, 3H), 2.95 (s, 1H), 2.75 (m, 2H), 7.01 (t, J=7.2 Hz, 2H), 1.82 (s, 3H); MS (ESI): m/z 502.0 [M+23]+.

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

実験手順: Followed the procedure described in General Scheme II, with modification. Step 1 was followed where the starting material was N-(4-(4-bromo-2-formylthiophen-3-yl)-3-methylphenyl)methanesulfonamide (Intermediate 4) instead of 3,4-dibromothiophene-2-carbaldehyde (Intermediate I), starting material 8A was 4-chloro-2-methoxyphenylboronic acid. After purification by column chromatography (PE:EtOAc=3:1) N-(4-(4-(4-chloro-2-methoxyphenyl)-2-formylthiophen-3-yl)-3-methylphenyl)methanesulfonamide (380 mg, yield 365.2%) was obtained. Step 3 of Scheme II was then followed with column conditions (PE: EtOAc=3:1) to afford (E)-ethyl 3-(4-(4-chloro-2-methoxyphenyl)-3-(2-methyl-4-(methylsulfonamido)phenyl)thiophen-2-yl)acrylate (280 mg, yield 63.4%). Step 4 of Scheme II gave 200 mg of product (yield 71%) followed by Step 5 (with purification by prep-HPLC) gave Example 10 (41.9 mg, 13% yield). 1H NMR (DMSO-d6 400 MHz): δ 9.73 (s, 1H), 7.38 (s, 1H), 6.93 (m, 4H), 6.90 (s, 1H), 6.86 (m, 1H), 3.5 (d, 3H), 2.95 (s, 1H), 2.75 (m, 2H), 7.01 (t, J=7.2 Hz, 2H), 1.82 (s, 3H); MS (ESI): m/z 502.0 [M+23]+.

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

実験手順: To a solution of (4-chloro-2-methoxyphenyl)boronic acid (1.0 g, 5.36 mmol) in dichloromethane (5 mL) at 0° C. was added boron tribromide (1 M in dichloromethane, 10 mL, 10 mmol). The reaction was stirred at 0° C. for 1 hour, then allowed to warm to room temperature and stirred as such for 18 hours. The reaction was quenched carefully with water. The resulting precipitate was collected by filtration, to give a white solid, 260 mg. The layers were separated and the organic layer was dried over Na2SO4 and concentrated in vacuo to give a white solid, 300 mg. The two batches of solid were combined to give the title compound as a white solid, 560 mg, in a 61% yield. This material was taken on to Preparation 18 without purification. to warm to room temperature stirred as such for 18 hours The reaction was quenched carefully with water The resulting precipitate was collected by filtration to give a white solid, 260 mg The layers were separated the organic layer was dried over Na2SO4 concentrated in vacuo to give a white solid, 300 mg

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

実験手順: To a solution of (4-chloro-2-methoxyphenyl)boronic acid (1.0 g, 5.36 mmol) in dichloromethane (5 mL) at 0° C. was added boron tribromide (1 M in dichloromethane, 10 mL, 10 mmol). The reaction was stirred at 0° C. for 1 hour, then allowed to warm to room temperature and stirred as such for 18 hours. The reaction was quenched carefully with water. The resulting precipitate was collected by filtration, to give a white solid, 260 mg. The layers were separated and the organic layer was dried over Na2SO4 and concentrated in vacuo to give a white solid, 300 mg. The two batches of solid were combined to give the title compound as a white solid, 560 mg, in a 61% yield. This material was taken on to Preparation 18 without purification. to warm to room temperature stirred as such for 18 hours The reaction was quenched carefully with water The resulting precipitate was collected by filtration to give a white solid, 260 mg The layers were separated the organic layer was dried over Na2SO4 concentrated in vacuo to give a white solid, 300 mg

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-Chloro-2-methoxyphenylboronic acid ethylene glycol ester: To a solution of 2-bromo-5-chloroanisole (4.43 g, 20 mmol) in dry THF (100 mL) at −78° C. was added dropwise t-BuLi (14.1 mL, 1.7 M, 23.97 mmol). The mixture was stirred for 10 min at −78° C. and trimethyl borate (2.23 mL, 20 mmol) was added. The cooling bath was removed and the mixture was stirred for 30 min from −78° C. to room temperature and then for 3 h with a water bath. Hydrochloric acid (6N, 8 mL) and brine were added. The mixture was extracted with ethyl acetate, dried and evaporated to give 4-chloro-2-methoxyphenylboronic acid as a brown solid (3.33 g, 17.88 mmol) in 89.4% yield. This boronic acid was mixed with ethylene glycol (1.1 g, 17.88 mmol) and toluene (150 mL). The mixture was refluxed for 2 h under N2 with the help of a Dean-Stark trap to remove water generated. After being cooled to room temperature, the solution was transferred to another dry flask and rotary evaporated to provide 4-Chloro-2-methoxyphenylboronic acid ethylene glycol ester as a brown liquid (3.6 g, 16.97 mmol) in 84.8% yield. The cooling bath was removed the mixture was stirred for 30 min from −78° C. to room temperature for 3 h with a water bath Hydrochloric acid (6N, 8 mL) and brine were added The mixture was extracted with ethyl acetate dried evaporated

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-Chloro-2-methoxyphenylboronic acid ethylene glycol ester: To a solution of 2-bromo-5-chloroanisole (4.43 g, 20 mmol) in dry THF (100 mL) at −78° C. was added dropwise t-BuLi (14.1 mL, 1.7 M, 23.97 mmol). The mixture was stirred for 10 min at −78° C. and trimethyl borate (2.23 mL, 20 mmol) was added. The cooling bath was removed and the mixture was stirred for 30 min from −78° C. to room temperature and then for 3 h with a water bath. Hydrochloric acid (6N, 8 mL) and brine were added. The mixture was extracted with ethyl acetate, dried and evaporated to give 4-chloro-2-methoxyphenylboronic acid as a brown solid (3.33 g, 17.88 mmol) in 89.4% yield. This boronic acid was mixed with ethylene glycol (1.1 g, 17.88 mmol) and toluene (150 mL). The mixture was refluxed for 2 h under N2 with the help of a Dean-Stark trap to remove water generated. After being cooled to room temperature, the solution was transferred to another dry flask and rotary evaporated to provide 4-Chloro-2-methoxyphenylboronic acid ethylene glycol ester as a brown liquid (3.6 g, 16.97 mmol) in 84.8% yield. The cooling bath was removed the mixture was stirred for 30 min from −78° C. to room temperature for 3 h with a water bath Hydrochloric acid (6N, 8 mL) and brine were added The mixture was extracted with ethyl acetate dried evaporated

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

実験手順: To a solution of (4-chloro-2-methoxyphenyl)boronic acid (1.0 g, 5.36 mmol) in dichloromethane (5 mL) at 0° C. was added boron tribromide (1 M in dichloromethane, 10 mL, 10 mmol). The reaction was stirred at 0° C. for 1 hour, then allowed to warm to room temperature and stirred as such for 18 hours. The reaction was quenched carefully with water. The resulting precipitate was collected by filtration, to give a white solid, 260 mg. The layers were separated and the organic layer was dried over Na2SO4 and concentrated in vacuo to give a white solid, 300 mg. The two batches of solid were combined to give the title compound as a white solid, 560 mg, in a 61% yield. This material was taken on to Preparation 18 without purification. to warm to room temperature stirred as such for 18 hours The reaction was quenched carefully with water The resulting precipitate was collected by filtration to give a white solid, 260 mg The layers were separated the organic layer was dried over Na2SO4 concentrated in vacuo to give a white solid, 300 mg