ethyl 2-chlorosulfonylacetate

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

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

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

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

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

Procedure: A solution of 54.6 g (0.29 mole) ethoxy carbonyl methanesulfonyl chloride in 250 ml methylene chloride is stirred at 0° under a nitrogen atmosphere while 46.8 g (0.29 mole) hexamethyldisilazane is added dropwise. The resulting cloudy solution is allowed to warm to 25° over one hour and then evaporated in vacuo to an oil which crystallizes: yield of the title product is 48.4 g (100%), mp 63°-67°; lit.1 mp 67°-68°, lit2 mp 66°-68°. is added dropwise to warm to 25° over one hour evaporated in vacuo to an oil which crystallizes

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: tert-Butylamine (7.9 mL, 75 mmol.) was dissolved in 50 mL of THF. The solution was cooled to −20° C. and (ethoxycarbonyl)methanesulfonyl chloride dissolved in 10 mL of THF was added slowly. The reaction mixture was allowed to warm to room temperature and stirred for 24 h. The mixture was filtered, and the filtrate concentrated in vacuo. The residue was purified by column chromatography (PE/EtOAc; 2:1) to afford ethyl-2-(N-tert-butylsulfamoyl)acetate (4.1 g, 43%). was added slowly to warm to room temperature The mixture was filtered the filtrate concentrated in vacuo The residue was purified by column chromatography (PE/EtOAc; 2:1)

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: tert-Butylamine (7.9 mL, 75 mmol.) was dissolved in 50 mL of THF. The solution was cooled to −20° C. and (ethoxycarbonyl)methanesulfonyl chloride dissolved in 10 mL of THF was added slowly. The reaction mixture was allowed to warm to room temperature and stirred for 24 h. The mixture was filtered, and the filtrate concentrated in vacuo. The residue was purified by column chromatography (PE/EtOAc; 2:1) to afford ethyl-2-(N-tert-butylsulfamoyl)acetate (4.1 g, 43%). was added slowly to warm to room temperature The mixture was filtered the filtrate concentrated in vacuo The residue was purified by column chromatography (PE/EtOAc; 2:1)

Conditions: temp:125.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (ethoxycarbonyl)methanesulfonic acid (10 g, 60 mmol.) and POCl3 (45 mL) was heated at 125° C. for 5 h. The mixture was cooled and filtered, and excess POCl3 was removed to give crude (ethoxycarbonyl)methanesulfonyl chloride (8.1 g, 80%) used directly without purification. The mixture was cooled filtered excess POCl3 was removed

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

Procedure: To a solution of 2-(2-amino-4-chloro-phenoxy)-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.030 g, 0.074 mmol) in dimethylformamide (0.5 ml) was added potassium carbonate (0.030 g, 0.239 mmol), chlorosulfonyl-acetic acid ethyl ester (0.02 g, 0.12 mmol) (for preparation, see: Helv. Chim. Acta., (1997) 80, 671 and Bull. Soc. Chim. Fr. (1975), 807) in dimethylformamide (0.5 ml) and finally catalytic dimethylaminopyridine. After 23 hours the reaction was diluted with ethyl acetate and washed with pH 7.0 phosphate buffer (0.05 M). The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude ester was then dissolved in 1:1 tetrahydrofuran:water (0.5 ml) and lithium hydroxide hydrate (0.004 g, 0.095 mmol) was added. After 19 hours the reaction was concentrated and the title compound purified by silica gel chromatography (0.006 g, LRMS: 528.3). washed with pH 7.0 phosphate buffer (0.05 M) The organic layer was dried over magnesium sulfate filtered concentrated The crude ester was then dissolved in 1:1 tetrahydrofuran After 19 hours the reaction was concentrated the title compound purified by silica gel chromatography (0.006 g, LRMS: 528.3)

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

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

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

Procedure: To a solution of 2-(2-amino-4-chloro-phenoxy)-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.030 g, 0.074 mmol) in dimethylformamide (0.5 ml) was added potassium carbonate (0.030 g, 0.239 mmol), chlorosulfonyl-acetic acid ethyl ester (0.02 g, 0.12 mmol) (for preparation, see: Helv. Chim. Acta., (1997) 80, 671 and Bull. Soc. Chim. Fr. (1975), 807) in dimethylformamide (0.5 ml) and finally catalytic dimethylaminopyridine. After 23 hours the reaction was diluted with ethyl acetate and washed with pH 7.0 phosphate buffer (0.05 M). The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude ester was then dissolved in 1:1 tetrahydrofuran:water (0.5 ml) and lithium hydroxide hydrate (0.004 g, 0.095 mmol) was added. After 19 hours the reaction was concentrated and the title compound purified by silica gel chromatography (0.006 g, LRMS: 528.3). washed with pH 7.0 phosphate buffer (0.05 M) The organic layer was dried over magnesium sulfate filtered concentrated The crude ester was then dissolved in 1:1 tetrahydrofuran After 19 hours the reaction was concentrated the title compound purified by silica gel chromatography (0.006 g, LRMS: 528.3)