ethyl N-methoxy-N-methylcarbamate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:-75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of n-butyllithium (2.5M, 39 ml, 0.096 mol) in 300 ml of ether cooled to -75° C. was added 4-bromopyridine (15.1 g,0.095 mol) in 100 ml of ether at such a rate to maintain the internal temperature below -50° C. The resulting mixture was stirred at -75° C. for 15 min., and N-methyl,N-methoxy-urethane (5.8 g, 0.043 mol) in 25 ml of ether was added over a 20 min period, and the mixtue was warmed to room temperature and then stirred for 2 h. The mixture was quenched with 300 ml of water and the layers were separated. The organic layer was extracted with 6N HCl solution, and the aqueous layer was basified with 10% NaOH solution. The basic solution was extracted with chloroform, organic layer dried over sodium sulfate, concentrated in vacuo, and purified by chromatography on silica (ethyl acetate) to afford 3.9 g (48.7%) of di-(4-pyridyl)ketone. to maintain the internal temperature below -50° C the mixtue was warmed to room temperature stirred for 2 h The mixture was quenched with 300 ml of water the layers were separated The organic layer was extracted with 6N HCl solution The basic solution was extracted with chloroform, organic layer dried over sodium sulfate concentrated in vacuo purified by chromatography on silica (ethyl acetate)

Conditions: temp:-75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of n-butyllithium (2.5M, 39 ml, 0.096 mol) in 300 ml of ether cooled to -75° C. was added 4-bromopyridine (15.1 g,0.095 mol) in 100 ml of ether at such a rate to maintain the internal temperature below -50° C. The resulting mixture was stirred at -75° C. for 15 min., and N-methyl,N-methoxy-urethane (5.8 g, 0.043 mol) in 25 ml of ether was added over a 20 min period, and the mixtue was warmed to room temperature and then stirred for 2 h. The mixture was quenched with 300 ml of water and the layers were separated. The organic layer was extracted with 6N HCl solution, and the aqueous layer was basified with 10% NaOH solution. The basic solution was extracted with chloroform, organic layer dried over sodium sulfate, concentrated in vacuo, and purified by chromatography on silica (ethyl acetate) to afford 3.9 g (48.7%) of di-(4-pyridyl)ketone. to maintain the internal temperature below -50° C the mixtue was warmed to room temperature stirred for 2 h The mixture was quenched with 300 ml of water the layers were separated The organic layer was extracted with 6N HCl solution The basic solution was extracted with chloroform, organic layer dried over sodium sulfate concentrated in vacuo purified by chromatography on silica (ethyl acetate)

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

Procedure: To a solution of 3-bromopyridine (9.84 g,0.062 mol) in 300 ml of ether cooled to -78° C. was added n-butyllithium (1.6M, 41 ml, 0.066 mol) and stirred for 30 min. N-Methyl,N-methoxy-urethane (3.76 g, 0.028 mol) in 20 ml of ether was added in 10 min, the mixture was stirred (-78° C.) for 1 h, allowed to warm to room temperature and stirred for 2 h. The reaction mixture was quenched with 6N HCl (100 ml) and stirred. The aqueous layer was basified with 10% NaOH solution, extracted with ethyl acetate (2×) and methylene dichloride. The organic layer was dried over sodium sulfate, concentrated in vacuo, and the residue was purified by chromatography on silica (ethyl acetate, 10% methanol/ethyl acetate) to afford 1,7 g (33%) of di-(3-pyridyl)ketone. the mixture was stirred (-78° C.) for 1 h stirred for 2 h The reaction mixture was quenched with 6N HCl (100 ml) stirred extracted with ethyl acetate (2×) and methylene dichloride The organic layer was dried over sodium sulfate concentrated in vacuo the residue was purified by chromatography on silica (ethyl acetate, 10% methanol/ethyl acetate)

Conditions: temp:-75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of n-butyllithium (2.5M, 39 mL, 0.096 mol) in 300 mL of ether cooled to -75° C. was added 4-bromopyridine (15.1 g, 0.095 mol) in 100 mL of ether at such a rate to maintain the internal temperature below -50° C. The resulting mixture was stirred at -75° C. for 15 min, and N-methyl,N-methoxyurethane (5.8 g, 0.043 mol) in 25 mL of ether was added over a 20 min period, and the mixture was warmed to room temperature and then stirred for 2 h. The mixture was quenched with 300 mL of water and the layers were separated. The organic layer was extracted with 6N HCl solution, and the aqueous layer was basified with 10% NaOH solution. The basic solution was extracted with chloroform, the organic layer dried over sodium sulfate, concentrated in vacuo, and purified by chromatography on silica (ethyl acetate) to afford 3.9 g (48.7%) of di-(4-pyridyl)ketone. to maintain the internal temperature below -50° C the mixture was warmed to room temperature stirred for 2 h The mixture was quenched with 300 mL of water the layers were separated The organic layer was extracted with 6N HCl solution The basic solution was extracted with chloroform the organic layer dried over sodium sulfate concentrated in vacuo purified by chromatography on silica (ethyl acetate)

Conditions: temp:-75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of n-butyllithium (2.5M, 39 mL, 0.096 mol) in 300 mL of ether cooled to -75° C. was added 4-bromopyridine (15.1 g, 0.095 mol) in 100 mL of ether at such a rate to maintain the internal temperature below -50° C. The resulting mixture was stirred at -75° C. for 15 min, and N-methyl,N-methoxyurethane (5.8 g, 0.043 mol) in 25 mL of ether was added over a 20 min period, and the mixture was warmed to room temperature and then stirred for 2 h. The mixture was quenched with 300 mL of water and the layers were separated. The organic layer was extracted with 6N HCl solution, and the aqueous layer was basified with 10% NaOH solution. The basic solution was extracted with chloroform, the organic layer dried over sodium sulfate, concentrated in vacuo, and purified by chromatography on silica (ethyl acetate) to afford 3.9 g (48.7%) of di-(4-pyridyl)ketone. to maintain the internal temperature below -50° C the mixture was warmed to room temperature stirred for 2 h The mixture was quenched with 300 mL of water the layers were separated The organic layer was extracted with 6N HCl solution The basic solution was extracted with chloroform the organic layer dried over sodium sulfate concentrated in vacuo purified by chromatography on silica (ethyl acetate)

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

Procedure: To a solution of 3-bromopyridine (9.84 g, 0.062 mol) in 300 mL of ether cooled to -78° C. was added n-butyllithium (1.6M, 41 mL, 0.066 mol) and stirred for 30 min. N-Methyl,N-methoxy-urethane (3.76 g, 0.028 mol) in 20 mL of ether was added in 10 min, the mixture was stirred (-78° C.) for 1 h, allowed to warm to room temperature and stirred for 2 h. The reaction mixture was quenched with 6N HCl (100 mL) and stirred. The aqueous layer was basified with 10% NaOH solution, extracted with ethyl acetate (2×) and methylene dichloride. The organic layer was dried over sodium sulfate, concentrated in vacuo, and the residue was purified by chromatography on silica (ethyl acetate, 10% methanol/ethyl acetate) to afford 1.7 g (33%) of di-(3-pyridyl)ketone. the mixture was stirred (-78° C.) for 1 h stirred for 2 h The reaction mixture was quenched with 6N HCl (100 mL) stirred extracted with ethyl acetate (2×) and methylene dichloride The organic layer was dried over sodium sulfate concentrated in vacuo the residue was purified by chromatography on silica (ethyl acetate, 10% methanol/ethyl acetate)

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

Procedure: To a solution of 3-bromopyridine (9.84 g, 0.062 mol) in 300 mL of ether cooled to -78° C. was added n-butyllithium (1.6M, 41 mL, 0.066 mol) and stirred for 30 min. N-Methyl,N-methoxy-urethane (3.76 g, 0.028 mol) in 20 mL of ether was added in 10 min, the mixture was stirred (-78° C.) for 1 h, allowed to warm to room temperature and stirred for 2 h. The reaction mixture was quenched with 6N HCl (100 mL) and stirred. The aqueous layer was basified with 10% NaOH solution, extracted with ethyl acetate (2×) and methylene dichloride. The organic layer was dried over sodium sulfate, concentrated in vacuo, and the residue was purified by chromatography on silica (ethyl acetate, 10% methanol/ethyl acetate) to afford 1.7 g (33%) of di-(3-pyridyl)ketone. the mixture was stirred (-78° C.) for 1 h stirred for 2 h The reaction mixture was quenched with 6N HCl (100 mL) stirred extracted with ethyl acetate (2×) and methylene dichloride The organic layer was dried over sodium sulfate concentrated in vacuo the residue was purified by chromatography on silica (ethyl acetate, 10% methanol/ethyl acetate)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The solution of 3-(5-fluoro-3-methyl-benzo[b]thiophen-2-yl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (2.09 g, 6.73 mmol) in THF (56 mL) is stirred at −78° C. Ethyl N-methoxy-N-methylcarbamate (4.48 g, 33.7 mmol) is added. LDA (10 mL, 20.1 mmol) is added dropwise to maintain reaction temperature at −75° C. The reaction is stirred at −78° C. for 1 hour. The mixture is quenched with H2O, filtered through celite with CH2Cl2. The collect solution is washed with H2O, dried over Na2SO4, filtered and concentrated. The crude is purified by ISCO (50-100% EtOAc/Hexane) to give the title compound (0.85 g, 31%). 1H NMR (CDCl3): δ 7.8 (dd, J=4.8, 8.5 Hz, 1H), 7.5 (dd, J=2.5, 9.7 Hz, 1H), 7.2 (m, 1H), 7.0 (s, 1H), 3.7 (s, 3H), 3.5 (s, 3H), 2.6 (s, 3H), 2.55 (s, 3H), 2.3 (s, 3H) ppm. MS (m/e): 399 (100%, M+1). to maintain reaction temperature at −75° C The mixture is quenched with H2O filtered through celite with CH2Cl2 The collect solution is washed with H2O dried over Na2SO4 filtered concentrated The crude is purified by ISCO (50-100% EtOAc/Hexane)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The solution of 3-(5-fluoro-3-methyl-benzo[b]thiophen-2-yl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (2.09 g, 6.73 mmol) in THF (56 mL) is stirred at −78° C. Ethyl N-methoxy-N-methylcarbamate (4.48 g, 33.7 mmol) is added. LDA (10 mL, 20.1 mmol) is added dropwise to maintain reaction temperature at −75° C. The reaction is stirred at −78° C. for 1 hour. The mixture is quenched with H2O, filtered through celite with CH2Cl2. The collect solution is washed with H2O, dried over Na2SO4, filtered and concentrated. The crude is purified by ISCO (50-100% EtOAc/Hexane) to give the title compound (0.85 g, 31%). 1H NMR (CDCl3): δ 7.8 (dd, J=4.8, 8.5 Hz, 1H), 7.5 (dd, J=2.5, 9.7 Hz, 1H), 7.2 (m, 1H), 7.0 (s, 1H), 3.7 (s, 3H), 3.5 (s, 3H), 2.6 (s, 3H), 2.55 (s, 3H), 2.3 (s, 3H) ppm. MS (m/e): 399 (100%, M+1). to maintain reaction temperature at −75° C The mixture is quenched with H2O filtered through celite with CH2Cl2 The collect solution is washed with H2O dried over Na2SO4 filtered concentrated The crude is purified by ISCO (50-100% EtOAc/Hexane)

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:-75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of n-butyllithium (2.5 M, 39 mL, 0.096 mol) in 300 mL of ether cooled to -75° C. was added 4-bromopyridine (15.1 g, 0.095 mol) in 100 mL of ether at such a rate to maintain the internal temperature below -50° C. The resulting mixture was stirred at -75° C. for 15 min, and N-methyl,N-methoxyurethane (5.8 g, 0.043 mol) in 25 mL of ether was added over a 20 min period, and the mixture was warmed to room temperature and then stirred for 2 h. The mixture was quenched with 300 mL of water and the layers were separated. The organic layer was extracted with 6 N HCl solution, and the aqueous layer was basified with 10% NaOH solution. The basic solution was extracted with chloroform, the organic layer dried over sodium sulfate, concentrated in vacuo, and purified by chromatography on silica (ethyl acetate) to afford 3.9 g (48.7%) of di-(4-pyridyl)ketone. to maintain the internal temperature below -50° C the mixture was warmed to room temperature stirred for 2 h The mixture was quenched with 300 mL of water the layers were separated The organic layer was extracted with 6 N HCl solution The basic solution was extracted with chloroform the organic layer dried over sodium sulfate concentrated in vacuo purified by chromatography on silica (ethyl acetate)