2,6-dichloro-N-methylaniline

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

Procedure: To 55.4 g (0.315 mole) of N-methyl-2,6-dichloroaniline is added 0.4 moles of ethereal HCl and 200 ml of m-cresol. The mixture is then stirred and heated on a steam bath to drive off the ether and excess hydrogen chloride. To the resultant mixture is then added 13.3 g (0.315 mole) of cyanamide then heated for 2 hours on a steam bath. The reaction mixture is then cooled, added to 150 ml of conc. sodium hydroxide solution, cooled and extracted with 2 liters of ether. The ether layer is washed with 2×1 liter of water, dried over sodium sulfate, charcoaled and evaporated. The residue is triturated with hexane and the precipitate is filtered off and washed with ether and dried to obtain 1-(2,6-dichlorophenyl)-1-methylguanidine hydrochloride. heated on a steam bath then heated for 2 hours on a steam bath The reaction mixture is then cooled cooled extracted with 2 liters of ether The ether layer is washed with 2×1 liter of water dried over sodium sulfate evaporated The residue is triturated with hexane the precipitate is filtered off washed with ether dried

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

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

Procedure: 2,6-Dichloroaniline (1.62 g, 10 mmol) in THF (5 mL) was cooled to −78° C. and treated with n-buthyllithium (8 mL of a 1.6 M solution in hexanes). After brief warming to −40° C. the solution was cooled again before addition of iodomethane (0.9 mL, ˜15 mmol). The mixture was allowed to warm to room temperature before addition of saturated ammonium chloride solution, extraction with ethyl acetate, drying over anhydrous MgSO4 and solvent evaporation. The resulting residue was purified by column chromatography (dichloromethane) to yield N-methyl-2,6-dichloroaniline (1.70 g, 96%). N-Methyl-2,6-dichloroaniline (0.86 g, 4.89 mmol) dissolved in ethyl acetate (10 mL) was added to an ice-cold solution of phosgene (5.0 mL of a 20% solution in toluene). Cooling was removed and the mixture stirred at room temperature for 10 min and then heated to reflux for 30 min. The solvent was removed and replaced by dichloromethane (20 mL) before drop-wise addition to a cooled (−40° C.) mixture of anhydrous hydrazine (0.64 g, 20 mmol) in dichloromethane (20 mL). The mixture was stirred at room temperature for 2 hours before addition of saturated sodium bicarbonate followed by phase separation and solvent removal to yield N-(2,6-dichlorophenyl)-N-methylhydrazinecarboxamide (1.06 g, 93%). The N-methylhydrazinecarboxamide product (500 mg, 2.14 mmol) was stirred with 4-chlorophenyl isocyanate (360 mg, 2.48 mmol) in dichloromethane (10 mL) at room temperature for 3 h. The resulting slurry was cooled (−10° C.), filtered, and washed with cold dichloromethane (10 mL) to give a white powder. A third of the product was treated with POCl3 (3 mL) and heated under reflux for 2½ hours, where after the yellow/brown solution was cooled and added to crushed ice (˜50 g) and neutralized by addition of ammonium hydroxide solution (25% m/V). Filtration and drying gave the crude product as an off-white powder (280 mg) which was purified by silica gel chromatography using 50%-75% EtOAc/hexanes to give 18 (122 mg, 48%). Cooling was removed heated to reflux for 30 min The solvent was removed replaced by dichloromethane (20 mL) before drop-wise addition to a cooled followed by phase separation and solvent removal

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

Procedure: 2,6-Dichloroaniline (1.62 g, 10 mmol) in THF (5 mL) was cooled to −78° C. and treated with n-buthyllithium (8 mL of a 1.6 M solution in hexanes). After brief warming to −40° C. the solution was cooled again before addition of iodomethane (0.9 mL, ˜15 mmol). The mixture was allowed to warm to room temperature before addition of saturated ammonium chloride solution, extraction with ethyl acetate, drying over anhydrous MgSO4 and solvent evaporation. The resulting residue was purified by column chromatography (dichloromethane) to yield N-methyl-2,6-dichloroaniline (1.70 g, 96%). N-Methyl-2,6-dichloroaniline (0.86 g, 4.89 mmol) dissolved in ethyl acetate (10 mL) was added to an ice-cold solution of phosgene (5.0 mL of a 20% solution in toluene). Cooling was removed and the mixture stirred at room temperature for 10 min and then heated to reflux for 30 min. The solvent was removed and replaced by dichloromethane (20 mL) before drop-wise addition to a cooled (−40° C.) mixture of anhydrous hydrazine (0.64 g, 20 mmol) in dichloromethane (20 mL). The mixture was stirred at room temperature for 2 hours before addition of saturated sodium bicarbonate followed by phase separation and solvent removal to yield N-(2,6-dichlorophenyl)-N-methylhydrazinecarboxamide (1.06 g, 93%). The N-methylhydrazinecarboxamide product (500 mg, 2.14 mmol) was stirred with 4-chlorophenyl isocyanate (360 mg, 2.48 mmol) in dichloromethane (10 mL) at room temperature for 3 h. The resulting slurry was cooled (−10° C.), filtered, and washed with cold dichloromethane (10 mL) to give a white powder. A third of the product was treated with POCl3 (3 mL) and heated under reflux for 2½ hours, where after the yellow/brown solution was cooled and added to crushed ice (˜50 g) and neutralized by addition of ammonium hydroxide solution (25% m/V). Filtration and drying gave the crude product as an off-white powder (280 mg) which was purified by silica gel chromatography using 50%-75% EtOAc/hexanes to give 18 (122 mg, 48%). Cooling was removed heated to reflux for 30 min The solvent was removed replaced by dichloromethane (20 mL) before drop-wise addition to a cooled followed by phase separation and solvent removal

Conditions: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2,6-Dichloroaniline (1.62 g, 10 mmol) in THF (5 mL) was cooled to −78° C. and treated with n-buthyllithium (8 mL of a 1.6 M solution in hexanes). After brief warming to −40° C. the solution was cooled again before addition of iodomethane (0.9 mL, ˜15 mmol). The mixture was allowed to warm to room temperature before addition of saturated ammonium chloride solution, extraction with ethyl acetate, drying over anhydrous MgSO4 and solvent evaporation. The resulting residue was purified by column chromatography (dichloromethane) to yield N-methyl-2,6-dichloroaniline (1.70 g, 96%). N-Methyl-2,6-dichloroaniline (0.86 g, 4.89 mmol) dissolved in ethyl acetate (10 mL) was added to an ice-cold solution of phosgene (5.0 mL of a 20% solution in toluene). Cooling was removed and the mixture stirred at room temperature for 10 min and then heated to reflux for 30 min. The solvent was removed and replaced by dichloromethane (20 mL) before drop-wise addition to a cooled (−40° C.) mixture of anhydrous hydrazine (0.64 g, 20 mmol) in dichloromethane (20 mL). The mixture was stirred at room temperature for 2 hours before addition of saturated sodium bicarbonate followed by phase separation and solvent removal to yield N-(2,6-dichlorophenyl)-N-methylhydrazinecarboxamide (1.06 g, 93%). The N-methylhydrazinecarboxamide product (500 mg, 2.14 mmol) was stirred with 4-chlorophenyl isocyanate (360 mg, 2.48 mmol) in dichloromethane (10 mL) at room temperature for 3 h. The resulting slurry was cooled (−10° C.), filtered, and washed with cold dichloromethane (10 mL) to give a white powder. A third of the product was treated with POCl3 (3 mL) and heated under reflux for 2½ hours, where after the yellow/brown solution was cooled and added to crushed ice (˜50 g) and neutralized by addition of ammonium hydroxide solution (25% m/V). Filtration and drying gave the crude product as an off-white powder (280 mg) which was purified by silica gel chromatography using 50%-75% EtOAc/hexanes to give 18 (122 mg, 48%). drying over anhydrous MgSO4 and solvent evaporation The resulting residue was purified by column chromatography (dichloromethane)

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

Procedure: To 55.4 g (0.315 mole) of N-methyl-2,6-dichloroaniline is added 0.4 moles of ethereal HCl and 200 ml of m-cresol. The mixture is then stirred and heated on a steam bath to drive off the ether and excess hydrogen chloride. To the resultant mixture is then added 13.3 g (0.315 mole) of cyanamide then heated for 2 hours on a steam bath. The reaction mixture is then cooled, added to 150 ml of conc. sodium hydroxide solution, cooled and extracted with 2 liters of ether. The ether layer is washed with 2×1 liter of water, dried over sodium sulfate, charcoaled and evaporated. The residue is triturated with hexane and the precipitate is filtered off and washed with ether and dried to obtain 1-(2,6-dichlorophenyl)-1-methylguanidine hydrochloride. heated on a steam bath then heated for 2 hours on a steam bath The reaction mixture is then cooled cooled extracted with 2 liters of ether The ether layer is washed with 2×1 liter of water dried over sodium sulfate evaporated The residue is triturated with hexane the precipitate is filtered off washed with ether dried

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

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

Procedure: To 55.4 g (0.315 mole) of N-methyl-2,6-dichloroaniline is added 0.4 moles of ethereal HCl and 200 ml of m-cresol. The mixture is then stirred and heated on a steam bath to drive off the ether and excess hydrogen chloride. To the resultant mixture is then added 13.3 g (0.315 mole) of cyanamide then heated for 2 hours on a steam bath. The reaction mixture is then cooled, added to 150 ml of conc. sodium hydroxide solution, cooled and extracted with 2 liters of ether. The ether layer is washed with 2×1 liter of water, dried over sodium sulfate, charcoaled and evaporated. The residue is triturated with hexane and the precipitate is filtered off and washed with ether and dried to obtain 1-(2,6-dichlorophenyl)-1-methylguanidine hydrochloride. heated on a steam bath then heated for 2 hours on a steam bath The reaction mixture is then cooled cooled extracted with 2 liters of ether The ether layer is washed with 2×1 liter of water dried over sodium sulfate evaporated The residue is triturated with hexane the precipitate is filtered off washed with ether dried

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

Procedure: To 55.4 g (0.315 mole) of N-methyl-2,6-dichloroaniline is added 0.4 mole of ethereal HCl and 200 ml of m-cresol. The mixture is then stirred and heated on a steam bath to drive off the ether and excess hydrogen chloride. To the resultant mixture is then added 13.3 g (0.315 mole) of cyanamide then heated for 2 hours on a steam bath. The reaction mixture is then cooled, added to 150 ml of conc. sodium hydroxide solution, cooled and extracted with 2 liters of ether. The ether layer is washed with 2 × 1 liter of water, dried over sodium sulfate, charcoaled and evaporated. The residue is triturated with hexane and the preciptate is filtered off and washed with ether and dried to obtain 1-(2,6-dichlorophenyl)-1-methylguanidine hydrochloride. heated on a steam bath then heated for 2 hours on a steam bath The reaction mixture is then cooled cooled extracted with 2 liters of ether The ether layer is washed with 2 × 1 liter of water dried over sodium sulfate evaporated The residue is triturated with hexane the preciptate is filtered off washed with ether dried

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

Procedure: 2,6-Dichloroaniline (1.62 g, 10 mmol) in THF (5 mL) was cooled to −78° C. and treated with n-buthyllithium (8 mL of a 1.6 M solution in hexanes). After brief warming to −40° C. the solution was cooled again before addition of iodomethane (0.9 mL, ˜15 mmol). The mixture was allowed to warm to room temperature before addition of saturated ammonium chloride solution, extraction with ethyl acetate, drying over anhydrous MgSO4 and solvent evaporation. The resulting residue was purified by column chromatography (dichloromethane) to yield N-methyl-2,6-dichloroaniline (1.70 g, 96%). N-Methyl-2,6-dichloroaniline (0.86 g, 4.89 mmol) dissolved in ethyl acetate (10 mL) was added to an ice-cold solution of phosgene (5.0 mL of a 20% solution in toluene). Cooling was removed and the mixture stirred at room temperature for 10 min and then heated to reflux for 30 min. The solvent was removed and replaced by dichloromethane (20 mL) before drop-wise addition to a cooled (−40° C.) mixture of anhydrous hydrazine (0.64 g, 20 mmol) in dichloromethane (20 mL). The mixture was stirred at room temperature for 2 hours before addition of saturated sodium bicarbonate followed by phase separation and solvent removal to yield N-(2,6-dichlorophenyl)-N-methylhydrazinecarboxamide (1.06 g, 93%). The N-methylhydrazinecarboxamide product (500 mg, 2.14 mmol) was stirred with 4-chlorophenyl isocyanate (360 mg, 2.48 mmol) in dichloromethane (10 mL) at room temperature for 3 h. The resulting slurry was cooled (−10° C.), filtered, and washed with cold dichloromethane (10 mL) to give a white powder. A third of the product was treated with POCl3 (3 mL) and heated under reflux for 2½ hours, where after the yellow/brown solution was cooled and added to crushed ice (˜50 g) and neutralized by addition of ammonium hydroxide solution (25% m/V). Filtration and drying gave the crude product as an off-white powder (280 mg) which was purified by silica gel chromatography using 50%-75% EtOAc/hexanes to give 18 (122 mg, 48%). Cooling was removed heated to reflux for 30 min The solvent was removed replaced by dichloromethane (20 mL) before drop-wise addition to a cooled followed by phase separation and solvent removal

Conditions: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2,6-Dichloroaniline (1.62 g, 10 mmol) in THF (5 mL) was cooled to −78° C. and treated with n-buthyllithium (8 mL of a 1.6 M solution in hexanes). After brief warming to −40° C. the solution was cooled again before addition of iodomethane (0.9 mL, ˜15 mmol). The mixture was allowed to warm to room temperature before addition of saturated ammonium chloride solution, extraction with ethyl acetate, drying over anhydrous MgSO4 and solvent evaporation. The resulting residue was purified by column chromatography (dichloromethane) to yield N-methyl-2,6-dichloroaniline (1.70 g, 96%). N-Methyl-2,6-dichloroaniline (0.86 g, 4.89 mmol) dissolved in ethyl acetate (10 mL) was added to an ice-cold solution of phosgene (5.0 mL of a 20% solution in toluene). Cooling was removed and the mixture stirred at room temperature for 10 min and then heated to reflux for 30 min. The solvent was removed and replaced by dichloromethane (20 mL) before drop-wise addition to a cooled (−40° C.) mixture of anhydrous hydrazine (0.64 g, 20 mmol) in dichloromethane (20 mL). The mixture was stirred at room temperature for 2 hours before addition of saturated sodium bicarbonate followed by phase separation and solvent removal to yield N-(2,6-dichlorophenyl)-N-methylhydrazinecarboxamide (1.06 g, 93%). The N-methylhydrazinecarboxamide product (500 mg, 2.14 mmol) was stirred with 4-chlorophenyl isocyanate (360 mg, 2.48 mmol) in dichloromethane (10 mL) at room temperature for 3 h. The resulting slurry was cooled (−10° C.), filtered, and washed with cold dichloromethane (10 mL) to give a white powder. A third of the product was treated with POCl3 (3 mL) and heated under reflux for 2½ hours, where after the yellow/brown solution was cooled and added to crushed ice (˜50 g) and neutralized by addition of ammonium hydroxide solution (25% m/V). Filtration and drying gave the crude product as an off-white powder (280 mg) which was purified by silica gel chromatography using 50%-75% EtOAc/hexanes to give 18 (122 mg, 48%). drying over anhydrous MgSO4 and solvent evaporation The resulting residue was purified by column chromatography (dichloromethane)