ethyl 2-methylsulfonylacetate

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

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 6.65 g (40 mmol) of ethyl methanesulphonylacetate and 5.72 g (48 mmol) of N,N-dimethylformamide dimethyl acetal are admixed and heated at 85° C. overnight. The solution is concentrated using a rotary evaporator, and the solid is comminuted with cyclohexane and filtered off with suction. The solution is concentrated a rotary evaporator the solid is comminuted with cyclohexane filtered off with suction

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

Procedure: Ethyl(methylsulfonyl)acetate (0.79 mL, 5.8 mmol, 1.0 equiv) was added dropwise via syringe to a mixture of sodium hydride (0.25 g 60% in mineral oil, 6.1 mmol, 1.1 equiv) in DMF (20 mL) at room temperature. The mixture was allowed to stir for 30 min, after which time 1-iodoethane (0.48 mL, 5.8 mmol, 1.0 equiv) was added. The reaction was allowed to stir overnight. A solution of saturated ammonium chloride (10 mL) and water (10 mL) were added, and the resulting mixture was extracted with diethyl ether (1×25 mL). The organic phase was separated, washed with water (1×10 mL), brine (1×5 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude material was purified by flash chromatography (2:1-0:1 heptane/ethyl acetate) to provide a white solid (0.29 g, 26%). MS (LCMS) m/z 195.4 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.05 (t, J=7.41 Hz, 3H) 1.33 (t, J=7.12 Hz, 3H) 1.99-2.25 (m, 2H) 2.99 (s, 3H) 3.66 (dd, J=10.54, 3.90 Hz, 1H) 4.30 (q, J=7.22 Hz, 2H). to stir overnight the resulting mixture was extracted with diethyl ether (1×25 mL) The organic phase was separated washed with water (1×10 mL), brine (1×5 mL) dried over anhydrous magnesium sulfate concentrated under reduced pressure The crude material was purified by flash chromatography (2:1-0:1 heptane/ethyl acetate)

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

Procedure: Ethyl(methylsulfonyl)acetate (0.79 mL, 5.8 mmol, 1.0 equiv) was added dropwise via syringe to a mixture of sodium hydride (0.25 g 60% in mineral oil, 6.1 mmol, 1.1 equiv) in DMF (20 mL) at room temperature. The mixture was allowed to stir for 30 min, after which time 1-iodoethane (0.48 mL, 5.8 mmol, 1.0 equiv) was added. The reaction was allowed to stir overnight. A solution of saturated ammonium chloride (10 mL) and water (10 mL) were added, and the resulting mixture was extracted with diethyl ether (1×25 mL). The organic phase was separated, washed with water (1×10 mL), brine (1×5 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude material was purified by flash chromatography (2:1-0:1 heptane/ethyl acetate) to provide a white solid (0.29 g, 26%). MS (LCMS) m/z 195.4 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.05 (t, J=7.41 Hz, 3H) 1.33 (t, J=7.12 Hz, 3H) 1.99-2.25 (m, 2H) 2.99 (s, 3H) 3.66 (dd, J=10.54, 3.90 Hz, 1H) 4.30 (q, J=7.22 Hz, 2H). to stir overnight the resulting mixture was extracted with diethyl ether (1×25 mL) The organic phase was separated washed with water (1×10 mL), brine (1×5 mL) dried over anhydrous magnesium sulfate concentrated under reduced pressure The crude material was purified by flash chromatography (2:1-0:1 heptane/ethyl acetate)

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

Procedure: A mixture of ethyl(methylsulphonyl)acetate (330 mg, 1.99 mmol) in 4 mL of DMF was treated with sodium hydride (88 mg, 60% dispersion in mineral oil, 2.19 mmol), until effervescence ceased in an ice bath under nitrogen. To this was added 4-fluoro-4′-(2-iodoethyl)biphenyl (650 mg, 1.99 mmol) as a solid and the residual material was dissolved by the addition of DMF (2 mL). The mixture was warmed to room temperature, then heated at 50° C. for 2 hours. The mixture was then cooled to room temperature, poured into 60 mL of 0.5N aqueous HCl and extracted 2×60 mL with ethyl acetate. The organic phase was dried over sodium sulfate filtered and concentrated in vacuo to yield a light yellow oil with some white solid particulates. The crude yield was 840 mg. The material was purified by flash chromatography on a 40 mm flash column using 120 g silica gel eluting with 0-50% ethyl acetate/heptane. This afforded the title compound as an oil (510 mg, 70.2%). MS (LC/MS) m/z 365.2 (M+1). ceased in an ice bath under nitrogen heated at 50° C. for 2 hours The mixture was then cooled to room temperature extracted 2×60 mL with ethyl acetate The organic phase was dried over sodium sulfate filtered concentrated in vacuo to yield a light yellow oil with some white solid particulates The material was purified by flash chromatography on a 40 mm flash column

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

Procedure: Sodium hydride (1.80 g, 45 mmol, 60% in mineral oil) was added in three portions to a solution of ethyl (methylsulfonyl)acetate (6.70 g, 40.3 mmol) in DMF (200 mL) at 0° C. The reaction was allowed to warm to room temperature and stirred for 1 hour. 1-(Benzyloxy)-4-(2-iodoethyl)benzene was added to the solution and the reaction was stirred overnight at rt. The reaction was quenched with 1N aqueous HCl (200 mL) and extracted with ethyl acetate (3×100 mL). The combined organics were dried (MgSO4), filtered and concentrated in vacuo. Chromatography on a Biotage 40 L column using 1:4 ethyl acetate in heptane afforded the title compound as a white solid (13.13 g, 86.5%). LC-MS m/z 375.2 (M−1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.34 (t, J=7.03 Hz, 3H) 2.31-2.47 (m, 2H) 2.55-2.68 (m, 1H) 2.70-2.80 (m, 1H) 3.00 (s, 3H) 3.66-3.80 (m, 1H) 4.18-4.38 (m, 2H) 5.06 (s, 2H) 6.92 (d, J=8.59 Hz, 2H) 7.09 (d, J=8.59 Hz, 2H) 7.31-7.47 (m, 5H). the reaction was stirred overnight at rt The reaction was quenched with 1N aqueous HCl (200 mL) extracted with ethyl acetate (3×100 mL) The combined organics were dried (MgSO4) filtered concentrated in vacuo

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

Procedure: A solution of ethyl(methylsulfonyl)acetate (1090 mg, 6.6 mmol, 1.0 equiv) in DMF (11 mL) was added dropwise to a mixture of 60% sodium hydride in mineral oil (315 mg, 7.9 mmol, 1.2 equiv) in DMF (11 mL) at 0° C. The reaction was warmed to room temperature and allowed to stir for 40 min. The reaction was cooled to 0° C. and a solution of 2-bromo-5-(2-iodoethyl)pyridine (2560 mg, 8.2 mmol, 1.3 equiv) in DMF (11 mL) was added dropwise, and the reaction was allowed to stir for 3 days. Saturated aqueous ammonium chloride solution (30 mL) was added, and the mixture was extracted with ethyl acetate (3×70 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (7:3 heptane/ethyl acetate) to provide the title compound as a white solid (1628 mg, 71%). MS (LCMS) m/z 352.1 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29-1.35 (m, 3H) 2.30-2.44 (m, 2H) 2.62-2.78 (m, 2H) 3.00 (s, 3H) 3.71 (dd, J=9.37, 4.68 Hz, 1H) 4.21-4.35 (m, 2H) 7.36-7.46 (m, 2H) 8.19 (d, J=1.56 Hz, 1H). The reaction was cooled to 0° C. to stir for 3 days the mixture was extracted with ethyl acetate (3×70 mL) The combined organic layers were washed with brine (60 mL) dried over anhydrous sodium sulfate filtered concentrated under reduced pressure The crude material was purified by flash chromatography (7:3 heptane/ethyl acetate)

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

Procedure: A solution of ethyl(methylsulfonyl)acetate (1090 mg, 6.6 mmol, 1.0 equiv) in DMF (11 mL) was added dropwise to a mixture of 60% sodium hydride in mineral oil (315 mg, 7.9 mmol, 1.2 equiv) in DMF (11 mL) at 0° C. The reaction was warmed to room temperature and allowed to stir for 40 min. The reaction was cooled to 0° C. and a solution of 2-bromo-5-(2-iodoethyl)pyridine (2560 mg, 8.2 mmol, 1.3 equiv) in DMF (11 mL) was added dropwise, and the reaction was allowed to stir for 3 days. Saturated aqueous ammonium chloride solution (30 mL) was added, and the mixture was extracted with ethyl acetate (3×70 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (7:3 heptane/ethyl acetate) to provide the title compound as a white solid (1628 mg, 71%). MS (LCMS) m/z 352.1 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29-1.35 (m, 3H) 2.30-2.44 (m, 2H) 2.62-2.78 (m, 2H) 3.00 (s, 3H) 3.71 (dd, J=9.37, 4.68 Hz, 1H) 4.21-4.35 (m, 2H) 7.36-7.46 (m, 2H) 8.19 (d, J=1.56 Hz, 1H). The reaction was cooled to 0° C. to stir for 3 days the mixture was extracted with ethyl acetate (3×70 mL) The combined organic layers were washed with brine (60 mL) dried over anhydrous sodium sulfate filtered concentrated under reduced pressure The crude material was purified by flash chromatography (7:3 heptane/ethyl acetate)

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

Procedure: 6.648 g of methylsulphonyl-acetic acid ethyl ester in 20 ml of DMF are added dropwise at -25°, within 25 minutes, to 1.745 g of sodium hydride dispersion (55% in oil) in 40 ml of DMF. The solution is subsequently stirred for 30 minutes at -25°, then 6.84 g of benzyl bromide in 40 ml of DMF are added dropwise. The reaction mixture is then stirred for 1 hour at room temperature, left to stand overnight and concentrated by evaporation. The residue is taken up in ethyl acetate, washed with water, dried, concentrated by evaporation and purified by flash chromatography on 700 g of silica gel 60 (eluant E). 1H-NMR (DMSO-d6): 1.1 ppm (t, 3H); 3.05 (s, 3H), 3.1-3.6 (m, 2H); 3.9-4.3 (m, 3H); 7.25 (m, 5H). The reaction mixture is then stirred for 1 hour at room temperature left to stand overnight concentrated by evaporation washed with water dried concentrated by evaporation purified by flash chromatography on 700 g of silica gel 60 (eluant E)

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

Procedure: 6.648 g of methylsulphonyl-acetic acid ethyl ester in 20 ml of DMF are added dropwise at -25°, within 25 minutes, to 1.745 g of sodium hydride dispersion (55% in oil) in 40 ml of DMF. The solution is subsequently stirred for 30 minutes at -25°, then 6.84 g of benzyl bromide in 40 ml of DMF are added dropwise. The reaction mixture is then stirred for 1 hour at room temperature, left to stand overnight and concentrated by evaporation. The residue is taken up in ethyl acetate, washed with water, dried, concentrated by evaporation and purified by flash chromatography on 700 g of silica gel 60 (eluant E). 1H-NMR (DMSO-d6): 1.1 ppm (t, 3H); 3.05 (s, 3H), 3.1-3.6 (m, 2H); 3.9-4.3 (m, 3H); 7.25 (m, 5H). The reaction mixture is then stirred for 1 hour at room temperature left to stand overnight concentrated by evaporation washed with water dried concentrated by evaporation purified by flash chromatography on 700 g of silica gel 60 (eluant E)

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

Procedure: 6.648 g of methylsulphonyl-acetic acid ethyl ester are added dropwise at -30°, within 30 minutes, to 1.745 g of sodium hydroxide dispersion (55% in oil) in 40 ml of DMF. The solution is subsequently stirred for 15 minutes, then heated and, within 150 minutes, under reflux, 7.4 g of 2-phenylethyl bromide in 10 ml of DMF are added dropwise thereto. The reaction mixture is then stirred for 20 minutes, acidified with 12 ml of glacial acetic acid and concentrated by evaporation. The residue is taken up in ethyl acetate, washed with water, dried over magnesium sulphate, concentrated by evaporation and purified by flash chromatography on 700 g of silica gel 60 (eluant D). 1H-NMR (DMSO-d6): 1.35 ppm (t, 3H), 2.6-2.9 (m, 2H); 3.75 (dxd, 1H); 4.25 (q, 2H) heated and, within 150 minutes under reflux The reaction mixture is then stirred for 20 minutes concentrated by evaporation washed with water dried over magnesium sulphate concentrated by evaporation purified by flash chromatography on 700 g of silica gel 60 (eluant D)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of ethylmethanesulfonylacetate (3.78 g, 22.74 mmol) was added slowly in a suspension of sodium hydride (60% in mineral oil, 1.07 g, 25 mmol) in dimethylacetamide under N2 atmosphere. The mixture was allowed to stir at room temperature until the evolution of hydrogen gas ceased, then heated to 90° C. for 30 min and cooled to room temperature. A solution of N-methylisatoic anhydride (4.43 g, 25 mmol) in dimethylacetamide was added slowly and heated overnight at 120° C. The mixture was cooled to room temperature, poured into ice water and acidified by cold 10% HCl. The solids formed were filtered and washed several times by water to yield 2.76 g (48%) of white solids. Mp 170° C. 1H NMR (DMSO-d6): δ 3.51 (s, 3H), 3.59 (s, 3H), 7.39 (t, J=7.4 Hz, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.84 (t, J=7.0 Hz, 1H), 8.09 (d, J=8.0 Hz, 1H). EIMS m/z 254 (M+1), 276 (M+23). Anal. (C11H11NO4S) C, H, N. cooled to room temperature heated overnight at 120° C The mixture was cooled to room temperature The solids formed were filtered washed several times by water