(2-phenoxyphenyl)boronic acid

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

実験手順: Prepared in 50% yield from 2-chloro-3-cyanopyridine and 2-phenoxyphenylboronic acid according to the procedure described for Example 153A. MS (ESI−) m/z 273.0 (M+H)+; 1H NMR (CDCl3) δ 6.94 (d, J=7.1 Hz, 1H), 7.06-7.11 (m, 3H), 7.20-7.44 (m, 5H), 7.54 (dd, J=7.5, 1.7 Hz, 1H), 8.00 (dd, J=8.1, 2.0 Hz, 1H), 8.86 (dd, J=5.1, 1.7 Hz, 1H).

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

実験手順: A mixture of Example 1e (152 mg, 0.40 mmol), 2-phenoxyphenylboronic acid (0.111 g, 0.520 mmol, 1.3 equivalents), Pd(PPh3)4 (0.023 g, 5 mol %) and cesium fluoride (0.182 g, 1.2 mmol) in DME (3 mL) and methanol (1.5 mL) was heated under microwave condition (120° C., 30 minutes). To this mixture was added potassium carbonate (0.055 g, 0.40 mmol) and water (1 mL) and the reaction mixture was reheated in the microwave oven at 120° C. for another 2 hours. The organic layer was separated and purified by flash chromatography (silica gel, ethyl acetate). The resulting material was triturated with acetone and filtered to provide 0.075 g of the title compound (59%). 1H NMR (500 MHz, DMSO-d6) δ 3.50 (s, 3H), 6.21-6.23 (m, 1H), 6.88 (d, J=7.62 Hz, 2H), 6.99-7.04 (m, 2H), 7.24-7.30 (m, 5H), 7.36-7.40 (m, 1H), 7.50 (dd, J=7.48, 1.68 Hz, 1H), 11.98 (s, 1H). MS (ESI+) m/z 317 (M+H)+. The organic layer was separated purified by flash chromatography (silica gel, ethyl acetate) The resulting material was triturated with acetone filtered

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

実験手順: A mixture of Example 1e (152 mg, 0.40 mmol), 2-phenoxyphenylboronic acid (0.111 g, 0.520 mmol, 1.3 equivalents), Pd(PPh3)4 (0.023 g, 5 mol %) and cesium fluoride (0.182 g, 1.2 mmol) in DME (3 mL) and methanol (1.5 mL) was heated under microwave condition (120° C., 30 minutes). To this mixture was added potassium carbonate (0.055 g, 0.40 mmol) and water (1 mL) and the reaction mixture was reheated in the microwave oven at 120° C. for another 2 hours. The organic layer was separated and purified by flash chromatography (silica gel, ethyl acetate). The resulting material was triturated with acetone and filtered to provide 0.075 g of the title compound (59%). 1H NMR (500 MHz, DMSO-d6) δ 3.50 (s, 3H), 6.21-6.23 (m, 1H), 6.88 (d, J=7.62 Hz, 2H), 6.99-7.04 (m, 2H), 7.24-7.30 (m, 5H), 7.36-7.40 (m, 1H), 7.50 (dd, J=7.48, 1.68 Hz, 1H), 11.98 (s, 1H). MS (ESI+) m/z 317 (M+H)+. The organic layer was separated purified by flash chromatography (silica gel, ethyl acetate) The resulting material was triturated with acetone filtered

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Into a 50 mL round bottom flask was weighed 100 mg of 2-Bromo-1,3-dimethyl-1H-pyrrole-4-carboxylic acid [4-(sulfamoyl)phenyl]-amide (0.27 mmol), 230 mg of (2-phenoxy)phenylboronic acid, potassium hydroxide (30.2 mg, 0.54 mmol), and DAPCy (J. Org Chem (2004), 69: 4330-4335) (6.2 mg, 4 Mol %) and Ethanol/DMF (3 ml, 50:50) was added. The solution was heated at 100° C. overnight. The reaction was cooled and washed into a separatory funnel with ethyl acetate and water. The ethyl acetate washed with water and brine, then was dried (MgSO4), and concentrated in vacuo. The resulting residue was purified by flash chromatography (SiO2), eluting with EtOAc/Hex 0-80% to afford the title compounds as a white solid (10 mg, 8%); 1H NMR (DMSO-d6): δ 7.88 (d, J=9 Hz, 2H), 7.77 (d, J=9 Hz, 2H), 7.60 (s, 1H), 7.43-7.37 (m, 1H), 7.32-7.20 (m, 4H), 7.04 (d, J=9 Hz, 2H), 6.85 (d, J=8 Hz, 2H), 3.52 (s, 3H), 3.04 (s, 3H), 2.20 (s, 3H); MS (ESI) m/z 461 [M+H]+ Into a 50 mL round bottom flask was weighed The reaction was cooled washed into a separatory funnel with ethyl acetate and water The ethyl acetate washed with water and brine was dried (MgSO4) concentrated in vacuo The resulting residue was purified by flash chromatography (SiO2) eluting with EtOAc/Hex 0-80%

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Into a 50 mL round bottom flask was weighed 100 mg of 2-Bromo-1,3-dimethyl-1H-pyrrole-4-carboxylic acid [4-(sulfamoyl)phenyl]-amide (0.27 mmol), 230 mg of (2-phenoxy)phenylboronic acid, potassium hydroxide (30.2 mg, 0.54 mmol), and DAPCy (J. Org Chem (2004), 69: 4330-4335) (6.2 mg, 4 Mol %) and Ethanol/DMF (3 ml, 50:50) was added. The solution was heated at 100° C. overnight. The reaction was cooled and washed into a separatory funnel with ethyl acetate and water. The ethyl acetate washed with water and brine, then was dried (MgSO4), and concentrated in vacuo. The resulting residue was purified by flash chromatography (SiO2), eluting with EtOAc/Hex 0-80% to afford the title compounds as a white solid (10 mg, 8%); 1H NMR (DMSO-d6): δ 7.88 (d, J=9 Hz, 2H), 7.77 (d, J=9 Hz, 2H), 7.60 (s, 1H), 7.43-7.37 (m, 1H), 7.32-7.20 (m, 4H), 7.04 (d, J=9 Hz, 2H), 6.85 (d, J=8 Hz, 2H), 3.52 (s, 3H), 3.04 (s, 3H), 2.20 (s, 3H); MS (ESI) m/z 461 [M+H]+ Into a 50 mL round bottom flask was weighed The reaction was cooled washed into a separatory funnel with ethyl acetate and water The ethyl acetate washed with water and brine was dried (MgSO4) concentrated in vacuo The resulting residue was purified by flash chromatography (SiO2) eluting with EtOAc/Hex 0-80%

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

実験手順: Prepared in 50% yield from 2-chloro-3-cyanopyridine and 2-phenoxyphenylboronic acid according to the procedure described for Example 153A. MS (ESI−) m/z 273.0 (M+H)+; 1H NMR (CDCl3) δ 6.94 (d, J=7.1 Hz, 1H), 7.06-7.11 (m, 3H), 7.20-7.44 (m, 5H), 7.54 (dd, J=7.5, 1.7 Hz, 1H), 8.00 (dd, J=8.1, 2.0 Hz, 1H), 8.86 (dd, J=5.1, 1.7 Hz, 1H).

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

実験手順: Prepared in 50% yield from 2-chloro-3-cyanopyridine and 2-phenoxyphenylboronic acid according to the procedure described for Example 153A. MS (ESI−) m/z 273.0 (M+H)+; 1H NMR (CDCl3) δ 6.94 (d, J=7.1 Hz, 1H), 7.06-7.11 (m, 3H), 7.20-7.44 (m, 5H), 7.54 (dd, J=7.5, 1.7 Hz, 1H), 8.00 (dd, J=8.1, 2.0 Hz, 1H), 8.86 (dd, J=5.1, 1.7 Hz, 1H).

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

実験手順: A mixture of 3-iodo-7-methoxy-1H-pyrrolo[2,3-c]pyridine (0.274 g, 1.0 mmol), 2-phenoxyphenylboronic acid (0.278 g, 1.3 mmol, 1.3 equivalents), Pd(PPh3)4 (0.058 g, 0.05 mmol), and cesium fluoride (0.456 g, 3 mmol) in dimethxoyethane (3 mL) and methanol (1.5 mL) was heated under microwave conditions (120° C., 30 minutes). The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 30% ethyl acetate/hexanes) to give the title compound (0.122 g, 38.6% yield). The reaction mixture was partitioned between water and ethyl acetate The aqueous layer was extracted three times with ethyl acetate The combined organic layers were washed with saturated aqueous sodium chloride dried over anhydrous magnesium sulfate filtered concentrated The residue was purified by flash column chromatography (silica gel, 30% ethyl acetate/hexanes)

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

実験手順: A mixture of 3-iodo-7-methoxy-1H-pyrrolo[2,3-c]pyridine (0.274 g, 1.0 mmol), 2-phenoxyphenylboronic acid (0.278 g, 1.3 mmol, 1.3 equivalents), Pd(PPh3)4 (0.058 g, 0.05 mmol), and cesium fluoride (0.456 g, 3 mmol) in dimethxoyethane (3 mL) and methanol (1.5 mL) was heated under microwave conditions (120° C., 30 minutes). The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 30% ethyl acetate/hexanes) to give the title compound (0.122 g, 38.6% yield). The reaction mixture was partitioned between water and ethyl acetate The aqueous layer was extracted three times with ethyl acetate The combined organic layers were washed with saturated aqueous sodium chloride dried over anhydrous magnesium sulfate filtered concentrated The residue was purified by flash column chromatography (silica gel, 30% ethyl acetate/hexanes)

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

実験手順: To a solution of (8-chloro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl-(4-morpholin-4-yl-phenyl)-amine (0.15 g, 0.45 mmol, 1 eq) in a mixture of ethanol:toluene (1:4) (10 ml) is taken in a dry pressure tube, palladium acetate (0.01 g, 0.045 mmol, 0.1 eq), anhydrous potassium carbonate (0.125 g, 0.90 mmol, 2 eq), 2-dicyclo-hexylphosphino-2′,6′-dimethoxybiphenyl, S-Phos (0.027 g, 0.06 mmol, 0.13 eq) and 2-phenoxyphenylboronic acid (0.19 g, 0.90 mmol, 2 eq) are added and the reaction mixture is degasified with nitrogen. The reaction mixture is heated to 120° C. for 1 hour. The reaction mixture is concentrated and the residue is taken in 25% methanol in dichloromethane (50 ml) and filtered through celite to remove the inorganics and the filtrate is concentrated and purified by silica column using (230-400) mesh to get the product as pale yellow solid. is taken in a dry pressure tube The reaction mixture is concentrated filtered through celite to remove the inorganics the filtrate is concentrated purified by silica column

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

実験手順: To a solution of (8-chloro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl-(4-morpholin-4-yl-phenyl)-amine (0.15 g, 0.45 mmol, 1 eq) in a mixture of ethanol:toluene (1:4) (10 ml) is taken in a dry pressure tube, palladium acetate (0.01 g, 0.045 mmol, 0.1 eq), anhydrous potassium carbonate (0.125 g, 0.90 mmol, 2 eq), 2-dicyclo-hexylphosphino-2′,6′-dimethoxybiphenyl, S-Phos (0.027 g, 0.06 mmol, 0.13 eq) and 2-phenoxyphenylboronic acid (0.19 g, 0.90 mmol, 2 eq) are added and the reaction mixture is degasified with nitrogen. The reaction mixture is heated to 120° C. for 1 hour. The reaction mixture is concentrated and the residue is taken in 25% methanol in dichloromethane (50 ml) and filtered through celite to remove the inorganics and the filtrate is concentrated and purified by silica column using (230-400) mesh to get the product as pale yellow solid. is taken in a dry pressure tube The reaction mixture is concentrated filtered through celite to remove the inorganics the filtrate is concentrated purified by silica column

反応条件: temp:105.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of bromide 22 (300 mg, 1.14 mmol), 2-phenoxyphenylboronic acid (366 mg, 1.71 mmol), PdCl2(PPh3)2 (80.0 mg, 0.114 mmol), LiCl (145 mg, 3.42 mmol) and 1M Na2CO3 (2.85 mL, 2.82 mmol) in toluene (5.4 mL) and EtOH (5.4 mL) was refluxed overnight (105° C. oil bath temp.). The reaction mixture was cooled, and separated between brine (20 mL) and ethyl acetate (30 mL). The aqueous layer was extracted with ethyl acetate (2×30 mL). The combined organic solutions were dried (MgSO4) and concentrated. The resulting solid was dry loaded on a silicagel column. Fractions containing the product were eluted using ethyl acetate:hexane (1:1) (gradient elution) to give a solid which was triturated with ether to give 23 as a white solid (186 mg, 46%); 1H NMR (400 MHz, CDCl3) δ 6.94 (dd, J=8.8, 1.0 Hz, 2H), 7.05 (t, J=7.4 Hz, 1H), 7.08 (s, 1H), 7.12 (dd, J=8.1, 1.1 Hz, 1H), 7.33-7.20 (m, 3H), 7.38 (dt, J=9.2, 1.7 Hz, 1H), 7.56 (dd, J=7.6, 1.8 Hz, 1H), 7.64 (d, J=2.4 Hz, 1H), 7.85 (s, 1H), 8.32 (d, J=2.0 Hz, 1H), 8.59 (d, J=2.0 Hz, 1H), 9.35-9.20 (bs, NH). The reaction mixture was cooled separated between brine (20 mL) and ethyl acetate (30 mL) The aqueous layer was extracted with ethyl acetate (2×30 mL) The combined organic solutions were dried (MgSO4) concentrated The resulting solid was dry Fractions containing the product were eluted to give a solid which was triturated with ether