5-Chloro-2-ethoxyphenylboronic acid

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Chloro-8-(2-ethoxy-5-chloro-phenyl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine and 2-ethoxy-5-chloro-phenylboronic acid in a manner analogous to Example 2c (0.46 g, 66%). MS=322 (MH)+.

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To an argon saturated solution of N-(4,6-dichloro-pyrimidin-2-yl)-methyl-amine (200 mg, 1.1 mmol), 5-chloro-2-ethoxy-phenylboronic acid (248 mg, 1.21 mmol) and palladium acetate (38 mg, 0.16 mmol) in dimethyl ethylene glycol (20 ml) was added a solution of sodium carbonate (240 mg, 2.2 mmol) in water (5 ml) followed by triphenylphosphine (66 mg, 0.33 mmol). After stirring at 70° C. under an argon atmosphere for 60 hours, the mixture was filtered through a pad of celite under suction and the filtrate was dried over magnesium sulfate. Evaporation of the solvent under reduced pressure provided [4-chloro-6-(5-chloro-2-ethoxy-phenyl)-pyrimidin-2-yl]-methyl-amine (300 mg, 90% yield). the mixture was filtered through a pad of celite under suction the filtrate was dried over magnesium sulfate Evaporation of the solvent under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 4,6-dichloro-pyrimidin-2-ylamine (0.50 g, 3.0 mmol), 5-chloro-2-ethoxy-phenyl boronic acid (0.61 g, 3.0 mmol), palladium (II) acetate (0.10 g, 0.46 mmol), and triphenylphosphine (0.24 g, 0.91 mmol) was added a solution of sodium carbonate (1.6 g, 15.2 mmol) in water (5 ml) followed by glyme (20 ml). The mixture was stirred under an argon atmosphere at room temperature for 3.5 hours. Acetone (20 ml) was added and the mixture was filtered through a pad of celite under suction. The filtrated was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with 15% ethyl acetate-hexane followed by 20% ethyl acetate-hexane to provide 4-chloro-6-(5-chloro-2-ethoxy-phenyl)-pyrimidin-2-ylamine (0.625 g, 73% yield) as a white powder. the mixture was filtered through a pad of celite under suction The filtrated was concentrated under reduced pressure the residue was purified by flash chromatography on silica gel eluting with 15% ethyl acetate-hexane

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of [4-(2-amino-6-chloro-pyrimidin-4-yl-amino)-phenyl]-methanol (6.0 g, 24 mmol), 5-chloro-2-ethoxy-phenyl boronic acid (7.7 g, 38.4 mmol), palladium (II) acetate (0.54 g, 2.4 mmol) and triphenylphosphine (1.26 g, 4.8 mmol) was added a solution of sodium carbonate (12.7 g, 120 mmol) in water (80 ml) followed by glyme (300 ml). The mixture was stirred under an argon atmosphere at 95-105° C. for 18 hours. Filtration and concentration of the filtrate yielded a residue which was purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (1:3) to provide the title compound (5.5 g, 62% yield) as a white powder. 1H NMR (DMSO-d6) δ 1.38 (t, 3H, J=6.9 Hz, CH3), 4.13 (q, 2H, J=6.9 Hz, CH2), 4.45 (d, 2H, J=5.7 Hz, CH2), 5.07 (t, 1H, J=5.7 Hz, OH), 6.26 (s, 2H, NH2), 6.77 (s, 1H, Ar), 7.14 (d, 1H, J-8.9 Hz, Ar), 7.24 (d, 2H, J=8.4 Hz, Ar), 7.41 (dd, 1H, J=8.8, 2.8 Hz, Ar), 7.64 (d, 2H, J=8.3 Hz, Ar), 7.93 (d, 1H, J=2.8 Hz, Ar), 9.12 (s, 1H, NH). Filtration and concentration of the filtrate yielded a residue which was purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (1:3)

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To an argon saturated solution of N-(4,6-dichloro-pyrimidin-2-yl)-methyl-amine (200 mg, 1.1 mmol), 5-chloro-2-ethoxy-phenylboronic acid (248 mg, 1.21 mmol) and palladium acetate (38 mg, 0.16 mmol) in dimethyl ethylene glycol (20 ml) was added a solution of sodium carbonate (240 mg, 2.2 mmol) in water (5 ml) followed by triphenylphosphine (66 mg, 0.33 mmol). After stirring at 70° C. under an argon atmosphere for 60 hours, the mixture was filtered through a pad of celite under suction and the filtrate was dried over magnesium sulfate. Evaporation of the solvent under reduced pressure provided [4-chloro-6-(5-chloro-2-ethoxy-phenyl)-pyrimidin-2-yl]-methyl-amine (300 mg, 90% yield). the mixture was filtered through a pad of celite under suction the filtrate was dried over magnesium sulfate Evaporation of the solvent under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 4,6-dichloro-pyrimidin-2-ylamine (0.50 g, 3.0 mmol), 5-chloro-2-ethoxy-phenyl boronic acid (0.61 g, 3.0 mmol), palladium (II) acetate (0.10 g, 0.46 mmol), and triphenylphosphine (0.24 g, 0.91 mmol) was added a solution of sodium carbonate (1.6 g, 15.2 mmol) in water (5 ml) followed by glyme (20 ml). The mixture was stirred under an argon atmosphere at room temperature for 3.5 hours. Acetone (20 ml) was added and the mixture was filtered through a pad of celite under suction. The filtrated was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with 15% ethyl acetate-hexane followed by 20% ethyl acetate-hexane to provide 4-chloro-6-(5-chloro-2-ethoxy-phenyl)-pyrimidin-2-ylamine (0.625 g, 73% yield) as a white powder. the mixture was filtered through a pad of celite under suction The filtrated was concentrated under reduced pressure the residue was purified by flash chromatography on silica gel eluting with 15% ethyl acetate-hexane

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of [4-(2-amino-6-chloro-pyrimidin-4-yl-amino)-phenyl]-methanol (6.0 g, 24 mmol), 5-chloro-2-ethoxy-phenyl boronic acid (7.7 g, 38.4 mmol), palladium (II) acetate (0.54 g, 2.4 mmol) and triphenylphosphine (1.26 g, 4.8 mmol) was added a solution of sodium carbonate (12.7 g, 120 mmol) in water (80 ml) followed by glyme (300 ml). The mixture was stirred under an argon atmosphere at 95-105° C. for 18 hours. Filtration and concentration of the filtrate yielded a residue which was purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (1:3) to provide the title compound (5.5 g, 62% yield) as a white powder. 1H NMR (DMSO-d6) δ 1.38 (t, 3H, J=6.9 Hz, CH3), 4.13 (q, 2H, J=6.9 Hz, CH2), 4.45 (d, 2H, J=5.7 Hz, CH2), 5.07 (t, 1H, J=5.7 Hz, OH), 6.26 (s, 2H, NH2), 6.77 (s, 1H, Ar), 7.14 (d, 1H, J-8.9 Hz, Ar), 7.24 (d, 2H, J=8.4 Hz, Ar), 7.41 (dd, 1H, J=8.8, 2.8 Hz, Ar), 7.64 (d, 2H, J=8.3 Hz, Ar), 7.93 (d, 1H, J=2.8 Hz, Ar), 9.12 (s, 1H, NH). Filtration and concentration of the filtrate yielded a residue which was purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (1:3)

Conditions: temp:200.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 5-chloro-2-ethoxyphenylboronic acid (601 mg, 3.0 mmol), palladium (II) acetate (33 mg, 0.15 mmol) and (R)-1-(4-bromophenyl)ethylamine (295 mg, 1.5 mmol) in water (4 ml) was heated for 5 min at 200° C. in a Smithcreator microwave oven. The reaction mixture was diluted with dichloromethane and purified on a Strata™ 5 g/20 ml SCX column (eluted with 2M ammonia in methanol) to give (R)-1-(5′-chloro-2′-ethoxy-biphenyl-4-yl)-ethylamine (341 mg, 1.2 mmol, 82%). To a solution of 1-(5′-chloro-2′-ethoxy-biphenyl-4-yl)-ethylamine (30 mg, 0.1 mmol) in dichloromethane (0.75 ml) was added triethylamine (36 mg, 0.35 mmol) and 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride (30 mg, 0.13 mmol) in dichloromethane (0.5 ml). The reaction mixture was then agitated at room temperature for 16 h and quenched with acetic acid (200 μl). Purification by preparatory LCMS and removal of solvent under reduced pressure gave the title compound (21 mg, 0.04 mmol, 40%): 1H NMR (400 MHz, DMSO-d6): δ 8.25 (d, 1H), 7.32-7.37 (m, 3H), 7.21-7.24 (m, 3H), 7.10 (d, 1H), 4.35 (m, 1H), 4.05 (m, 2H), 2.20 (s, 3H), 1.26-1.35 (m, 6H) ppm; MS (ESI) m/z: value [M+H]+. purified on a Strata™ 5 g/20 ml SCX column (eluted with 2M ammonia in methanol)

Conditions: temp:200.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 5-chloro-2-ethoxyphenylboronic acid (601 mg, 3.0 mmol), palladium (II) acetate (33 mg, 0.15 mmol) and (R)-1-(4-bromophenyl)ethylamine (295 mg, 1.5 mmol) in water (4 ml) was heated for 5 min at 200° C. in a Smithcreator microwave oven. The reaction mixture was diluted with dichloromethane and purified on a Strata™ 5 g/20 ml SCX column (eluted with 2M ammonia in methanol) to give (R)-1-(5′-chloro-2′-ethoxy-biphenyl-4-yl)-ethylamine (341 mg, 1.2 mmol, 82%). To a solution of 1-(5′-chloro-2′-ethoxy-biphenyl-4-yl)-ethylamine (30 mg, 0.1 mmol) in dichloromethane (0.75 ml) was added triethylamine (36 mg, 0.35 mmol) and 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride (30 mg, 0.13 mmol) in dichloromethane (0.5 ml). The reaction mixture was then agitated at room temperature for 16 h and quenched with acetic acid (200 μl). Purification by preparatory LCMS and removal of solvent under reduced pressure gave the title compound (21 mg, 0.04 mmol, 40%): 1H NMR (400 MHz, DMSO-d6): δ 8.25 (d, 1H), 7.32-7.37 (m, 3H), 7.21-7.24 (m, 3H), 7.10 (d, 1H), 4.35 (m, 1H), 4.05 (m, 2H), 2.20 (s, 3H), 1.26-1.35 (m, 6H) ppm; MS (ESI) m/z: value [M+H]+. purified on a Strata™ 5 g/20 ml SCX column (eluted with 2M ammonia in methanol)

Conditions: temp:200.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 5-chloro-2-ethoxyphenylboronic acid (601 mg, 3.0 mmol), palladium (II) acetate (33 mg, 0.15 mmol) and (R)-1-(4-bromophenyl)ethylamine (295 mg, 1.5 mmol) in water (4 ml) was heated for 5 min at 200° C. in a Smithcreator microwave oven. The reaction mixture was diluted with dichloromethane and purified on a Strata™ 5 g/20 ml SCX column (eluted with 2M ammonia in methanol) to give (R)-1-(5′-chloro-2′-ethoxy-biphenyl-4-yl)-ethylamine (341 mg, 1.2 mmol, 82%). To a solution of 1-(5′-chloro-2′-ethoxy-biphenyl-4-yl)-ethylamine (30 mg, 0.1 mmol) in dichloromethane (0.75 ml) was added triethylamine (36 mg, 0.35 mmol) and 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride (30 mg, 0.13 mmol) in dichloromethane (0.5 ml). The reaction mixture was then agitated at room temperature for 16 h and quenched with acetic acid (200 μl). Purification by preparatory LCMS and removal of solvent under reduced pressure gave the title compound (21 mg, 0.04 mmol, 40%): 1H NMR (400 MHz, DMSO-d6): δ 8.25 (d, 1H), 7.32-7.37 (m, 3H), 7.21-7.24 (m, 3H), 7.10 (d, 1H), 4.35 (m, 1H), 4.05 (m, 2H), 2.20 (s, 3H), 1.26-1.35 (m, 6H) ppm; MS (ESI) m/z: value [M+H]+. purified on a Strata™ 5 g/20 ml SCX column (eluted with 2M ammonia in methanol)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: This compound was prepared from tert-butyl 5-((diphenoxyphosphoryl)oxy)-2H-1,4-oxazine-4(3H)-carboxylate and 5-chloro-2-ethoxyphenylboronic acid using a procedure similar to that described in Example 2 (Steps 1-3a) above. The product was isolated as a white solid (24% yield); 1H-NMR (d6-DMSO) 1.05 (9H, brs), 1.26 (3H, t), 3.62 (2H, t), 3.92 (2H, q), 4.15 (2H, t), 6.21 (1H, s), 6.90 (1H, d), 7.09 (1H, m), 7.22 (1H, dd); 13C-NMR (d6-DMSO) 14.9, 27.7, 63.9, 67.05, 67.1, 111.9, 126.9, 127.3, 132.0; MS ES(+) 240.0 (M++1); Anal. Calcd for C17H22ClNO4: C, 60.09; H, 6.53; N, 4.12. Found: C, 59.60; H, 6.46; N, 4.35. IR λmax=1701, 1394 cm−1.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Chloro-8-(2-ethoxy-5-chloro-phenyl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine and 2-ethoxy-5-chloro-phenylboronic acid in a manner analogous to Example 2c (0.46 g, 66%). MS=322 (MH)+.