N-ethylsulfamoyl chloride

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

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a round bottom flask equipped with a magnetic stirrer and nitrogen were added toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxy-5-methyl-phenyl) ester (prepared in Example RRR; 6.86 g, 19.6 mmol), Et2O (100 mL), and NEt3 (3.25 mL, 23.4 mmol), respectively. The solution was cooled to 0° C. and treated rapidly with a solution of (ethyl amino)sulfonyl chloride (3.37 g, 23.4 mmol) in Et2O (10 mL). The reaction was stirred for 30 minutes and then filtered. The solids were washed with Et2O, and the filtrate was concentrated. The resulting residue was dried in a high vacuum oven at 40° C. overnight to yield the title compound. 1H NMR (CDCl3) δ 1.15 (s, 9 H), 1.23 (t, 3 H) 2.19 (s, 3 H), 2.35 (s, 3 H), 3.30 (m, 2 H), 4.75 (br t, 1 H), 7.16 (s, 1 H), 7.19 (s, 1 H), 7.32 (d, 2 H), 7.39 (d, 2 H). To a round bottom flask equipped with a magnetic stirrer filtered The solids were washed with Et2O the filtrate was concentrated The resulting residue was dried in a high vacuum oven at 40° C. overnight

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

Procedure: A solution of 18.8 g (0.2 mole) of phenol and 38.4 g (0.27 mole) of ethylaminosulfonyl chloride (Preparation 25) in 150 ml of toluene was stirred and heated at reflux for 16 hr. The solution was cooled and then treated with 250 ml of a 20% sodium bicarbonate solution. The layers were separated and the organic layer was washed successively with 250 ml of a 20% sodium bicarbonate solution, two 300-ml portions of water and dried (magnesium sulfate). The solvent was evaporated under reduced pressure and the oily residue was purified by chromatography (4.5×105 cm glass column; 550 g of silica gel; ethyl acetate-hexanes, 1:16). Fractions containing the product were combined and the solvents evaporated under reduced pressure to give 28.5 g (71%) of the title compound as a colorless liquid. Elemental analysis suggested that the product contained water. heated at reflux for 16 hr The solution was cooled The layers were separated the organic layer was washed successively with 250 ml of a 20% sodium bicarbonate solution, two 300-ml portions of water dried (magnesium sulfate) The solvent was evaporated under reduced pressure the oily residue was purified by chromatography (4.5×105 cm glass column; 550 g of silica gel; ethyl acetate-hexanes, 1:16) Fractions containing the product the solvents evaporated under reduced pressure

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a round bottom flask equipped with a magnetic stirrer and nitrogen were added toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxy-5-methyl-phenyl) ester (prepared in Example RRR; 6.86 g, 19.6 mmol), Et2O (100 mL), and NEt3 (3.25 mL, 23.4 mmol), respectively. The solution was cooled to 0° C. and treated rapidly with a solution of (ethyl amino)sulfonyl chloride (3.37 g, 23.4 mmol) in Et2O (10 mL). The reaction was stirred for 30 minutes and then filtered. The solids were washed with Et2O, and the filtrate was concentrated. The resulting residue was dried in a high vacuum oven at 40° C. overnight to yield the title compound. 1H NMR (CDCl3) δ 1.15 (s, 9 H), 1.23 (t, 3 H) 2.19 (s, 3 H), 2.35 (s, 3 H), 3.30 (m, 2 H), 4.75 (br t, 1 H), 7.16 (s, 1 H), 7.19 (s, 1 H), 7.32 (d, 2 H), 7.39 (d, 2 H). To a round bottom flask equipped with a magnetic stirrer filtered The solids were washed with Et2O the filtrate was concentrated The resulting residue was dried in a high vacuum oven at 40° C. overnight

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

Procedure: To 5.18 g (20 mmole) 4-(hexafluoro-2-hydroxy-2-propyl)aniline and 3.44 g (24 mmole) N-ethylsulfamoyl chloride in 30 ml CHCl3, add 2.18 g (24 mmole) Et3N in 20 ml CHCl3 and stir for 16 hours. Dilute with CHCl3 and wash with 1N HCl. Dry, concentrate and recrystallize from Et2O-hexane to yield the product; m.p. 178°-179° C. wash with 1N HCl Dry concentrate recrystallize from Et2O-hexane to yield the product

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a round bottom flask equipped with a magnetic stirrer and nitrogen were added toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxy-5-methyl-phenyl) ester (prepared in Example RRR; 6.86 g, 19.6 mmol), Et2O (100 mL), and NEt3 (3.25 mL, 23.4 mmol), respectively. The solution was cooled to 0° C. and treated rapidly with a solution of (ethyl amino)sulfonyl chloride (3.37 g, 23.4 mmol) in Et2O (10 mL). The reaction was stirred for 30 minutes and then filtered. The solids were washed with Et2O, and the filtrate was concentrated. The resulting residue was dried in a high vacuum oven at 40° C. overnight to yield the title compound. 1H NMR (CDCl3) δ 1.15 (s, 9 H), 1.23 (t, 3 H) 2.19 (s, 3 H), 2.35 (s, 3 H), 3.30 (m, 2 H), 4.75 (br t, 1 H), 7.16 (s, 1 H), 7.19 (s, 1 H), 7.32 (d, 2 H), 7.39 (d, 2 H). To a round bottom flask equipped with a magnetic stirrer filtered The solids were washed with Et2O the filtrate was concentrated The resulting residue was dried in a high vacuum oven at 40° C. overnight

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

Procedure: A solution of 18.8 g (0.2 mole) of phenol and 38.4 g (0.27 mole) of ethylaminosulfonyl chloride (Preparation 25) in 150 ml of toluene was stirred and heated at reflux for 16 hr. The solution was cooled and then treated with 250 ml of a 20% sodium bicarbonate solution. The layers were separated and the organic layer was washed successively with 250 ml of a 20% sodium bicarbonate solution, two 300-ml portions of water and dried (magnesium sulfate). The solvent was evaporated under reduced pressure and the oily residue was purified by chromatography (4.5×105 cm glass column; 550 g of silica gel; ethyl acetate-hexanes, 1:16). Fractions containing the product were combined and the solvents evaporated under reduced pressure to give 28.5 g (71%) of the title compound as a colorless liquid. Elemental analysis suggested that the product contained water. heated at reflux for 16 hr The solution was cooled The layers were separated the organic layer was washed successively with 250 ml of a 20% sodium bicarbonate solution, two 300-ml portions of water dried (magnesium sulfate) The solvent was evaporated under reduced pressure the oily residue was purified by chromatography (4.5×105 cm glass column; 550 g of silica gel; ethyl acetate-hexanes, 1:16) Fractions containing the product the solvents evaporated under reduced pressure

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

Procedure: A solution of 18.8 g (0.2 mole) of phenol and 38.4 g (0.27 mole) of ethylaminosulfonyl chloride (Preparation 25) in 150 ml of toluene was stirred and heated at reflux for 16 hr. The solution was cooled and then treated with 250 ml of a 20% sodium bicarbonate solution. The layers were separated and the organic layer was washed successively with 250 ml of a 20% sodium bicarbonate solution, two 300-ml portions of water and dried (magnesium sulfate). The solvent was evaporated under reduced pressure and the oily residue was purified by chromatography (4.5×105 cm glass column; 550 g of silica gel; ethyl acetate-hexanes, 1:16). Fractions containing the product were combined and the solvents evaporated under reduced pressure to give 28.5 g (71%) of the title compound as a colorless liquid. Elemental analysis suggested that the product contained water. heated at reflux for 16 hr The solution was cooled The layers were separated the organic layer was washed successively with 250 ml of a 20% sodium bicarbonate solution, two 300-ml portions of water dried (magnesium sulfate) The solvent was evaporated under reduced pressure the oily residue was purified by chromatography (4.5×105 cm glass column; 550 g of silica gel; ethyl acetate-hexanes, 1:16) Fractions containing the product the solvents evaporated under reduced pressure

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

Procedure: 4-Amino-6-chloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidine (100 mg) was dissolved in THF (5 ml) and DCM (5 ml). DBU (46 mg) and DMAP (37 mg) were added followed by the addition of ethyl-sulfamoylchloride (prepared from ethylamine hydrochloride and sulfuryl chloride). The mixture was stirred for 12 h at r.t. The solvent was evaporated. Water and a 10% solution of citric acid were added followed by extraction with EtOAc and DCM. The combined organic layers were dried over sodium sulfate and the solvent was evaporated under reduced pressure. After purification of the residue by chromatography over silicagel with EtOAc/methanol/ammonia=4:1:0.5, ethyl sulfamic acid-[6-chloro-5-(o-methoxy-phenoxy)-2-(4-pyridyl)-pyrimidin-4-yl]-amide (10 mg) was obtained. tR=4.31 min, (LC); [M+H]+=436.14 (ES+). The solvent was evaporated Water and a 10% solution of citric acid were added followed by extraction with EtOAc and DCM The combined organic layers were dried over sodium sulfate the solvent was evaporated under reduced pressure After purification of the residue by chromatography over silicagel with EtOAc/methanol/ammonia=4:1:0.5

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

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

Procedure: 4-Amino-6-chloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidine (100 mg) was dissolved in THF (5 ml) and DCM (5 ml). DBU (46 mg) and DMAP (37 mg) were added followed by the addition of ethyl-sulfamoylchloride (prepared from ethylamine hydrochloride and sulfuryl chloride). The mixture was stirred for 12 h at r.t. The solvent was evaporated. Water and a 10% solution of citric acid were added followed by extraction with EtOAc and DCM. The combined organic layers were dried over sodium sulfate and the solvent was evaporated under reduced pressure. After purification of the residue by chromatography over silicagel with EtOAc/methanol/ammonia=4:1:0.5, ethyl sulfamic acid-[6-chloro-5-(o-methoxy-phenoxy)-2-(4-pyridyl)-pyrimidin-4-yl]-amide (10 mg) was obtained. tR=4.31 min, (LC); [M+H]+=436.14 (ES+). The solvent was evaporated Water and a 10% solution of citric acid were added followed by extraction with EtOAc and DCM The combined organic layers were dried over sodium sulfate the solvent was evaporated under reduced pressure After purification of the residue by chromatography over silicagel with EtOAc/methanol/ammonia=4:1:0.5

Conditions: temp:22.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 197.8 parts of pyridine are introduced in the course of 20 minutes at -10° C., whilst stirring, into a solution of 196.3 parts of acetyl chloride in 1,350 parts of methylene chloride. 359 parts of ethylsulfamic acid chloride are then added at the same temperature. The reaction mixture is stirred for half an hour at 0° C. and one hour at 22° C. Thereafter, the mixture is stirred for 5 minutes with 800 parts of water at 9° C. and pH 1. The organic phase is then separated off from the 2-phase mixture formed, and is filtered and subjected to fractional distillation. 367 parts (79% of theory) of N-acetyl-N-ethylsulfamic acid chloride, of boiling point 34°-40° C./0.11 mbar and nD25 =1.4595, are obtained. The organic phase is then separated off from the 2-phase mixture formed is filtered subjected to fractional distillation